AU2014308991B2

AU2014308991B2 - Antiviral compounds

Info

Publication number: AU2014308991B2
Application number: AU2014308991A
Authority: AU
Inventors: Daniele Andreotti; Leonid Beigelman; Haiying He; Carmela NAPOLITANO; Karin Ann Stein; Anh Truong; Guangyi Wang
Original assignee: Janssen Biopharma Inc
Current assignee: Janssen Biopharma Inc
Priority date: 2013-08-21
Filing date: 2014-08-19
Publication date: 2019-02-14
Anticipated expiration: 2034-08-19
Also published as: CA2921294A1; US11021444B2; CA2921294C; NZ736517A; CN105636936B; MX2016002199A; SG11201600977XA; US20220363640A1; KR20160039685A; BR112016003348B1; UA123854C2; JP2016538316A; KR102455034B1; EP3036220A4; CN105636936A; BR112016003348A2; US20150065504A1; MX2021002168A; IL244163A0; EA201690224A1

Abstract

Disclosed herein are new antiviral compounds, together with pharmaceutical compositions that include one or more antiviral compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds. Examples of paramyxovirus infection include an infection caused by human respiratory syncytial virus (RSV).

Description

Description [0004] Respiratory viral infections, including upper and lower respiratory tract viral infections are a leading cause of death of millions of people each year. Upper respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory system below the vocal cords, including the trachea, primary bronchi and lungs. Human respiratory syncytial virus (RSV) is a common cause of

-1respiratory tract infections. Up to 60% of human infants are infected with RSV within their first year of life. Children and adults are also infected with RSV, ------------------------------2014308991 05 Apr 2017

-laWO 2015/026792

PCT/US2014/051642 where it is often manifesting as a lower respiratory tract infection with possible complications of bronchiolitis. RSV infections can be particularly severe in infants and elderly patients.

RSV is a negative-sense, single-stranded RNA virus classified within the Paramyxoviridae family, which also includes viruses that cause Newcastle disease, parainfluenza, mumps, measles, and canine distemper.

SUMMARY [0005] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0006] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the paramyxovirus viral infection an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for ameliorating and/or treating a paramyxovirus viral infection. Still other embodiments described herein relate to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, that can be used for ameliorating and/or treating a paramyxovirus viral infection. Yet still other embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. Some embodiments disclosed herein relate to a method of inhibiting the replication of a paramyxovirus that can include contacting a cell infected with the paramyxovirus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the paramyxovirus viral infection can be caused by a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a

-9WO 2015/026792

PCT/US2014/051642 pneumovirus (including a respiratory syncytial viral infection), a metapneumovirus, hendravirus. nipahvirus, measles, sendai virus, mumps, a human parainfluenza virus (HPIV1, HPIV-2, HPIV-3 and HPIV-4) and/or a metapneumovirus.

[0007] Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include administering to a subject suffering from the viral infection an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein. Some embodiments disclosed herein relate to a method of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.

BRIEF DESCRIPTION OF THE DRAWINGS [0008] Figure 1 illustrates examples of compounds of Formula (I), or pharmaceutically acceptable salt of any of the foregoing compounds.

DETAILED DESCRIPTION [0009] Paramyxoviridae family is a family of single stranded RNA viruses. Several genera of the paramyxoviridae family include henipavirus, morbillivirus. respirovirus, rubulavirus, pneumovirus and metapneumovirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites. Species of henipavirus include hendravirus and nipahvirus. A species of morbillivirus is measles. Species of respirovirus include sendai virus and human parainfluenza viruses 1 and 3; and species of rubulavirus include mumps virus and human parainfluenza viruses 2 and 4. A species of metapneumovirus is human metapneumovirus.

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PCT/US2014/051642 [0010] Human Respiratory Syncytial Virus (RSV). a species of pneumovirus, can cause respiratory infections, and can be associated with bronchiolitis and pneumonia. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decrease in appetite, and wheezing. RSV is the most common cause of bronchiolitis and pneumonia in children under one year of age in the world, and can be the cause of tracheobronchitis in older children and adults. In the United States, between 75,000 and 125,000 infants are hospitalized each year with RSV. Among adults older than 65 years of age, an estimated 14.000 deaths and 177,000 hospitalizations have been attributed to RSV.

[0011] Treatment options for people infected with RSV are currently limited. Antibiotics, usually prescribed to treat bacterial infections, and over-the-counter medication are not effective in treating RSV. In severe cases, a nebulized bronchodilator, such as albuterol, may be prescribed to relieve some of the symptoms, such as wheezing. RespiGram® (RSV-1G1V, Medlmmune, approved for high risk children younger than 24 months of age), Synagis® (palivizumab, Medlmmune, approved for high risk children younger than 24 months of age), and Virzole® (ribavirin by aerosol, ICN pharmaceuticals) have been approved for treatment of RSV.

[0012] Symptoms of the measles include fever, cough, runny nose, red eyes and a generalized rash. Some individuals with measles can develop pneumonia, ear infections and bronchitis. Mumps leads to swelling of the salivary glands. Symptoms of mumps include fever, loss of appetite and fatigue. Individuals are often immunized against measles and mumps via a three-part MMR vaccine (measles, mumps, and rubella). Human parainfluenza virus includes four serotypes types, and can cause upper and lower respiratory tract infections. Human parainfluenza virus 1 (HPIV-1) can be associated with croup; human parainfluenza virus 3 (HPIV-3) can be associated with bronchiolitis and pneumonia. According to the Centers of Disease Control and Prevention (CDC), there are no vaccines against human parainfluenza virus.

Definitions [0013] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are

-4incorporated by reference in their entirety unless stated otherwise. In the event that there are a

PCT/US2014/051642

Received 18/06/2015 plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0014] As used herein, any R group(s) such as, without limitation, R¹, R², R³, R⁴,

represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two R groups are described as being taken together the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R^a and R^b of an NR^a R^b group are indicated to be taken together, it means that they are covalently bonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defined previously.

[0015] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, acylalkyl, hydroxy, alkoxy, alkoxyalkyl, aminoalkyl, amino acid, aryl, heteroaryl, heterocyciyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxyalkyl, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

[0016] As used herein, “C_a to Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms

AMENDED SHEET IPEA/AU

WO 2015/026792

PCT/US2014/051642 in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl, ring(s) of the heteroaryl or ring(s) of the heteroalicyclyl can contain from “a” to b”. inclusive, carbon atoms. Thus, for example, a C| to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH₃-, CH3CH2-. CH3CH2CH2-. (CH₃)2CH-. CH₃CH₂CH₂CH2-. CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If no a” and “b” are designated with regard to an alkyl, alkenyl, alkvnyl. cycloalkyl cycloalkenyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these definitions is to be assumed.

[0017] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g.. “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom. 2 carbon atoms. 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only. “C1-C4 alkyl indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl. iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

[0018] As used herein, “alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenvl. An alkenyl group may be unsubstituted or substituted.

|0019] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethvnyl and propynyl. An alkynyl group may be unsubstituted or substituted.

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PCT/US2014/051642 [0020] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalky l group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0021] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pielectron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0022] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicvclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C₆-C|4 aryl group, a C₆-Cio aryl group, or a C₍, aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0023] As used herein, “heteroaryl” refers to a monocyclic or multicvclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one, two. three or more heteroatoms, that is. an element other than carbon, including but not limited to. nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s). 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to. those described herein and the following: furan, lurazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-7WO 2015/026792

PCT/US2014/051642 oxadiazole, 1,2,4-oxadiazole, thiazole. 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazolc, benzopyrazolc, isoxazolc, benzoisoxazole. isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline.

quinoxaline, cinnoline and triazine. A heteroary1 group may be substituted or unsubstituted.

[0024] As used herein, “heterocyclyl” or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thiosystems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such heterocyclyl’· or heteroalicyclyl” groups include, but are not limited to. those described herein and the following: 1,3-dioxin, 1.3-dioxane, 1,4-dioxane, 1.2-dioxolane, 1,3-dioxolane. 1,4dioxolane, 1,3-oxathiane, 1,4-oxathiin. 1.3-oxathiolane. 1.3-dithiole. 1,3-dithiolane, 1,4oxathiane, tetrahydro-1,4-thiazine. 1.3-thiazinane, 2H-1,2-oxazine, maleimide. succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3.5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine. oxazoline. oxazolidine. oxazolidinone, thiazoline. thiazolidine, morpholine, oxirane, piperidine AOxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine. tetrahydropyran. 4H-pvran. tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3.4-methylenedioxyphenyl).

[0025] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of

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PCT/US2014/051642 an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phcnylalkyl and naphthylalkyl.

[0026] As used herein, “heteroaralkyl” and heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent. via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl. furylalkyl, thienylalkyl, pyrrolylalkyl. pyridylalkyl, isoxazolylalkyl, imidazolylalkyl and their benzo-fused analogs.

[0027] A “heteroalicyclyl(alkyl)” and heterocyclyl (alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heteroalicyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl). piperidin-4-yl(ethyl), piperidin-4-yl(propyl). tetrahydro-2H-thiopyran-4-yl (methyl). and 1,3-thiazinan-4-yl(methyl).

[0028] Lower alkylene groups” are straight-chained -CH?- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH?-), ethylene (-CH2CH2-), propylene (CH2CH2CH2-), and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of substituted.'’ [0029] As used herein, alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl). aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkvl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), nbutoxv, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxv. An alkoxy may be substituted or unsubstituted.

[0030] As used herein, acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acrvl. An acyl may be substituted or unsubstituted.

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PCT/US2014/051642 [0031] As used herein, “acylalkyl” refers to an acyl connected, as a substituent, via a lower alkylene group. Examples include aryl-C(=O)-(CIl2)_n- and heteroaryl-C(=O)(CH2)_n-. where n is an integer in the range of 1 to 6.

[0032] As used herein, “alkoxyalkyl” refers to an alkoxy group connected, as a substituent, via a lower alkylene group. Examples include Cm alkyl-O-(CH₂)_n- .wherein n is an integer in the range of 1 to 6.

[0033] As used herein, “aminoalkyl” refers to an optionally substituted amino group connected, as a substituent, via a lower alkylene group. Examples include H₂N(CH2)_n,wherein n is an integer in the range of 1 to 6.

[0034] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to. 2-hydroxyethvl. 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0035] As used herein, “haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g.. mono-haloalkyl. di-haloalkyl and trihaloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloro-fluoroalkyl. chloro-difl uoroalkyl and 2fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0036] As used herein, “haloalkoxy” refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxv). Such groups include but are not limited to. chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy. chloro-fluoroalkyl. chlorodifluoroalkoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0037] A “sulfenyl” group refers to an “-SR group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.

[0038] A “sulfinyl group refers to an “-S(=O)-R group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

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PCT/US2014/051642 [0039] A “sulfonyl” group refers to an “SO?R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0040] An “O-carboxy” group refers to a “RC(=O)O-” group in wflich R can be hydrogen, an alkyl, an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl). as defined herein. An O-carboxy may be substituted or unsubstituted.

[0041] The terms ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0042] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

|0043] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.

[0044] A “trihalomethanesulfonamido” group refers to an “X.3CS(O)2N(Ra)- group wherein each X is a halogen, and Ra hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0045] The term “amino” as used herein refers to a -NH2 group.

[0046] As used herein, the term “hydroxy” refers to a -OH group.

[0047] A “cyano” group refers to a “-CN” group.

[0048] The term “azido” as used herein refers to a -N3 group.

[0049] An isocyanato” group refers to a “-NCO” group.

[0050] A “thiocyanato” group refers to a “-CNS” group.

[0051] An isothiocyanate” group refers to an “ -NCS” group.

[0052] A “carbonyl” group refers to a C=O group.

[0053] An “S-sulfonamido group refers to a “-SCBNIRaRb) group in which Ra and Rb can be independently hydrogen, an alkyl, an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclvl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

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PCT/US2014/051642 [0054] An “N-sulfonamido” group refers to a “RSC>2N(Ra)-” group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl). aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0055] An ‘Ό-carbamy Γ group refers to a ”-OC(=O)N(RaRb) group in which Ra and Rb can be independently hydrogen, an alkyl, an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0056] An “N-carbamyl group refers to an ROC(=O)N(Ra)-” group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl. a cycloalkyl, a cvcloalkenyl, ary l, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl! alkvl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

|0057] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RaRu)” group in which Ra and Rb can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cvcloalkyl, a cvcloalkenyl. aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0058] An “N-thiocarbamyl group refers to an “ROC(=S)N(Ra)-” group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cvcloalkenyl, aryl, heteroaryl. heterocyclyl. cycloalkyl(alkyl), aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0059] A “C-amido group refers to a “-C(=O)N(RaRb)” group in which Ra and Rb can be independently hydrogen, an alkyl, an alkenyl, an alkynyl. a cycloalkyl, a cycloalkenyl, aryl, heteroaryl. heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0060] An “N-amido” group refers to a “RC(=O)N(Ra)- group in which R and Ra can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cvcloalkenyl. ary l, heteroaryl, heterocyclyl. cycloalkyl(alkyl). aryl(alkyl). heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.

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PCT/US2014/051642 [0061] A urea” group refers to “N(R)-C(=O)-NRaRb group in which R can be hydrogen or an alkyl, and R,\ and Rb can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl. cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A urea may be substituted or unsubstituted.

[0062] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.

[0063] As used herein. ......” indicates a single or double bond, unless stated otherwise.

[0064] T he term “interferon is used herein as is commonly understood by one of ordinary skill in the art. Several types of interferons are known to those skilled in the art, such as Type 1 interferons, Type 2 interferons and Type 3 interferons. A non-limiting list of examples include: alpha-interferons, beta-interferons, delta-interferons, gamma interferons, lambda interferons, omega-interferons, tau-interferons, x-interferons, consensus interferons and asialo-interferons. Interferons can be pegylated. Examples of type 1 interferons include interferon alpha 1 A, interferon alpha 1B. interferon alpha 2A, interferon alpha 2B, pegylatedinterferon alpha 2a (PEGASYS, Roche), recombinant interferon alpha 2a (ROFERON, Roche), inhaled interferon alpha 2b (AERX. Aradigm). pegylated-interferon alpha 2b (ALBUFERON, Human Genome Sciences/Novartis. PEGINTRON. Schering), recombinant interferon alpha 2b (INTRON A, Schering), pegylated interferon alpha 2b (PEG-INTRON. Schering, V1RAFERONPEG, Schering), interferon beta-la (REBIF, Serono, Inc. and Pfizer), consensus interferon alpha (INFERGEN, Valeant Pharmaceutical). Examples of type 2 interferons include interferon gamma 1. interferon gamma 2 and pegylated interferon gamma; and examples of type 3 interferons include interferon lambda 1, interferon lambda 2 and interferon lambda 3.

[0065] Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

-13WO 2015/026792

PCT/US2014/051642 [0066] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC'-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).

[0067] As used herein, the term “amino acid’' refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, βarnino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to. alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to. ornithine, hypusine. 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine. alpha-propyl-glycine and norleucine. As used herein, “amino acid” also includes amino acids wherein the main-chain carboxylic acid group has been converted to an ester group.

[0068] The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molecule in order to prevent existing groups in the molecule from undergoing unwanted chemical reactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plenum Press. 1973, both of which are hereby incorporated by reference for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way. that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl: substituted benzyl: alkylcarbonvls and alkoxycarbonyls (e.g.. t-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g.. trimethvlsilyl. triethylsilyl, triisopropylsilyl. t-butyldimethylsilyl, tri-Aopropylsilyloxymethvl. [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or

-14WO 2015/026792

PCT/US2014/051642 mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3-dioxane, 1.3-dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrityl (MMTr); 4.4'-dimethoxytrityl (DMTr); 4.4'.4-trimethoxytrityl (TMTr); and those described herein).

[0069] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g.. hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine. tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0070] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ’including, without limitation,’ ’including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including.* ‘containing.* or ‘characterized by.’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes* should be interpreted as ‘includes but is not limited to;* the term ‘example* is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting

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PCT/US2014/051642 list thereof; and use of terms like ‘preferably,’ ‘preferred,' ‘desired,’ or ‘desirable,’ and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising” is to be interpreted synonymously with the phrases having at least or including at least. When used in the context of a process, the term comprising means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term comprising means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every⁷ one of those items be present in the grouping, but rather should be read as ‘and/or' unless expressly stated otherwise. Similarly, a group of items linked with the conjunction ‘or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or' unless expressly stated otherwise.

[0071] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0072] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry⁷ is not expressly' indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or

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PCT/US2014/051642 more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0073] Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.

[0074] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g.. hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0075] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as. for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0076] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

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PCT/US2014/051642 [0077] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

Compounds

Formula (1) [0078] Some embodiments disclosed herein relate to a compound of Formula (T). or a pharmaceutically acceptable salt thereof, having the structure:

(lb), _R2d

A can be

(Td);

selected from an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted aryl(Ci-2 alkyl), an optionally substituted heteroaryl and an optionally substituted heterocyclyl; Y can be selected from an optionally substituted cvcloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl; R^la. R^lb. R^lc and R^ld can be each independently hydrogen or an unsubstituted C|-4 alkyl; R^2a, R^2al, R^2b, R^2bl, R^2c, R^2cl, R^2d and R^2dl can be each independently selected from hydrogen, an optionally substituted C|_₄ alkyl, an optionally substituted aryl(C|_6 alkyl),

-18WO 2015/026792

PCT/US2014/051642 an optionally substituted heterocyclyl(C|_6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or R^2al can be hydrogen, and R^la and R^2a can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl, R^2bl can be hydrogen, and R^lb and R^2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl; —......between X^la and X^2d represents a single or double bond between X^la and

X²'¹: -------- between X^2a and X^3a represents a single or double bond between X^2a and X^3d;

provided that —......between X^la and X^2a and -------- between X^2d and X '^a cannot be both double bonds and at least one of--------is a double bond; when--------between X^ld and X^2a represents a double bond and--------between X^2d and X^3a is a single bond, then X^la can be N (nitrogen) or CR^4dl, X^2a can be N (nitrogen) or CR^?a and X’^a can be NR^6al, C(=O) or CR^6a2R^6a’; _and when .......- between X^la and X^2a represents a single bond and .......

between X^2a and X^3a is a double bond, then X^la can be NR^4a or CR^4a2R^4a3, X^2a can be N (nitrogen) or CR^?a and X’^a can be N (nitrogen) or CR^6a; or X^la, X^2a and X^ja can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=O), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining X^la and X^ja together; with the proviso that the valencies of X^la, X^2a and X’^a can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted Cm alkyl, and X^la, X^2a and X^ja are uncharged; R‘^,a and R^ddl can be each independently selected from hydrogen, hydroxy, halogen, amino, an optionally substituted Cm alkyl, an optionally substituted C2-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C1. 4 alkoxy, -O-carboxy, an optionally substituted heteroaryl, an optionally substituted nh₂ heterocyclyl. CIllH. CF? and

N oh

O , provided that R'^,a and R^3al cannot be both hydrogen; or R^,a and R’^al can together form =N-OR^a; or R^3a and R^jal can together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or

-19WO 2015/026792

PCT/US2014/051642 an optionally substituted 6 membered ring; R^4d, R^4dl, R^4d2 and R^4dJ can be each independently hydrogen or an unsubstituted C1.4 alkyl; R^?a and R^?al can be each independently be hydrogen or an unsubstituted Cm alkyl; R^6a and R^6al can be each independently hydrogen, an optionally substituted Cm alkyl or an optionally substituted alkoxyalkyl; R^6a2 and R^6aj can be each independently hydrogen or an unsubstituted Cm alkyl; X^lb. X^2b and X^jb can be each independently C (carbon), N (nitrogen). O (oxygen) or C(=O). and form a bi-cyclic ring selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining X^lb and X^3b together; provided that at least one of X^lb, X^2h and X^jb comprises a nitrogen atom; with the proviso that the valencies of X^lb, X^2band X'^lh can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted Cm alkyl, and X^lb, X^2b and X^3b are uncharged; R’^e and R'^J can be each independently⁷ selected from hydrogen, hydroxy, halogen, amino, an optionally substituted Cm alkyl, an optionally substituted C7-4 alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Cm alkoxy, -Ocarboxy. an optionally substituted heteroaryl, an optionally substituted heterocyclyl, CHF2, __NH₂

F ^N OH

CF3 and 0 , provided that R’^c and R^dCl cannot be both hydrogen; or R’^c and R^jcl can together form =N-OR^C; or R^Jt and R^jcl can together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring; R^a and R^c can be each independently hydrogen or an unsubstituted Cm alkyl; R^4e and R^x can be taken together to form an unsubstituted ary l, an unsubstituted heteroary l or an optionally substituted heterocyclyl; ΊΙ can be N or CH; m^d can be 0 or 1; and ring B^d can be an optionally substituted C5 cycloalkyl; ring B^dl can be an optionally substituted pyridinyl; and provided that when L is Formula (lie), then Y is absent.

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PCT/US2014/051642

Formula (la) [0079] In some embodiments, L can be Formula (la):

[0080] In some embodiments of Formula (la), X^la can be CR^4al or CR^4d2R^4ai, X^2a can be N (nitrogen), and X’^a can be CR^6d or CR^6a2R^6dJ. In some embodiments of Formula (la),........between X^ld and X^?a can be a single bond,........between X^?a and X'^a can be a double bond, X^ld can be CR^4a2R^4dJ, X^2a can be N (nitrogen), and X^jb can be CR^6d. In other embodiments of Formula (la), .......- between X^la and X^2a can be a double bond, .......between X^2a and X^ja can be a single bond, X^la can be CR^4al. X^2b can be N (nitrogen), and X^jb can be CR^6a2R^6aj. In some embodiments, including those of this paragraph, R^?a can be hydrogen. In some embodiments including those of this paragraph. R^sal can be hydrogen. In some embodiments, -X^la------X^2a------X^Jil- can be -CH2-N=CH- or -CH=N-CH2-. In other embodiments, -X^la-.....X^2a------X^3a- can be -N=N-CH₂-. -N=CH-CH₂- or -N=CH-NH-. In still other embodiments, -X^la.....-X^2a------X^3a- can be -CH₂-CH=N-, -NH-CH=NH- or -NHN=CH-. In some embodiments, X^ld, X^2d and X'^1d can be each independently C (carbon), N (nitrogen), O (oxygen) or C(=O), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclvl by joining X^la and X '^a together: with the proviso that the valencies of X^la, X^2aand X^,a can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted Ομ alkyl; and X^la, X^2d and ,X '^a are uncharged.

WO 2015/026792

PCT/US2014/051642

Formula (lai) [0081] In some embodiments, L of Formula (la) can be Formula (Ial): R^1a R^3a

⁰ R^2a (Ial) wherein: X^la, X^2a and X^ja can be each independently C (carbon). N (nitrogen). O (oxygen) or C(=O), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyciyl by joining X^la and X^3d together; with the proviso that the valencies of X^,d. X^2d and X^3a can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted Cm alkyl: and X^la. X^2a and X^3a are uncharged.

[0082] In some embodiments of Formula (Ial ). X^la can be C. X^2a can be N and X’^a can be C. In some embodiments of Formula (lai ).--------between X^la and X^2a can be a single bond.--------between X^2a and X^ja can be a double bond, X^la can be C, X^2a can be N and X‘^,a can be C. In other embodiments of Formula (Ial).--------between X^ld and X^2d can be a double bond,--------between X^2a and X^3a can be a single bond. X^la can be C. X^2a can be

N and X^ia can be C. In still other embodiments of Formula (Ial),--------between X^la and

X^2a can be a single bond,.....— between X^2a and X’^a can be a single bond, X^la can be C, X^2a can be O and X’^a can be C. In some embodiments, the valencies of X^la, X^2a and X^3a can be each independently satisfied with hydrogen or an unsubstituted C i .4 alkyl, such as CH3.

[0083] In some embodiments, the ring or ring system of Formula (lai ) can be an optionally substituted and. In other embodiments, the ring or ring system of Formula (Ial) can be an optionally substituted mono-cyclic heteroaryl. In still other embodiments, the ring or ring system of Formula (Ial) can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, the ring or ring system of Formula (Ial) can be an optionally substituted monocyclic heterocyciyl. In some embodiments, the ring or ring system of Formula (Ial) can be an optionally substituted bi-cyclic heterocyciyl.

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PCT/US2014/051642

X^1a x^3a [0084] In some embodiments of Formula (lai). can be selected from an optionally substituted

an optionally substituted

an optionally substituted an optionally substituted

. an optionally substituted

. an optionally substituted

, an optionally substituted an optionally substituted

optionally substituted

optionally substituted

and an optionally substituted

wherein R^AI, R^A2. R^Aj

A4 . · and R can be each independently hydrogen or an unsubstituted C i .6 alkyl.

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PCT/US2014/051642 substituted

In some embodiments,

can be an optionally . In some embodiments.

can be substituted with one or more substituents selected from amino, mono-substituted amino, di-substituted amino, hydroxyalkyl, alkyl and alkoxy. In some embodiments.

an unsubstituted substituted

. In other embodiments.

substituted can be an optionally substituted can be or a substituted

or an optionally

In some embodiments, . R^ja can be hydroxy and R^jal can be selected from amino, an unsubstituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3.6 cycloalkyl (for example, cyclopropyl), an unsubstituted Cm alkoxy (such as OCH3). hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole).

[0086] In some embodiments, when one of R’^d and R’^dl is H and the other of R’^d and R^Jdl is OH. then is not an unsubstituted

other embodiments, when one of R^Jd and R^3dl is H, then the other of R^J‘‘ and R‘

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PCT/US2014/051642

is not an optionally substituted pyrimidine. In cannot

In some embodiments,

Formula (Ia2) [0087] In some embodiments. L of Formula (la) can be Formula (la2):

R^7a2 (Ia2) wherein R^7al, R'^a2 and R'^aj can be each independently selected from hydrogen, halogen, hydroxy, an optionally substituted C|_s alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted C2-8 alkynyl. an optionally substituted C3.6 cycloalkvl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl. an optionally substituted hydroxyalkyl, an optionally substituted C]_g alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, haio(Ci-s alkyl), haloalkyl, an optionally substituted O-amido and an optionally substituted C-carboxy. In some embodiments, R^7alcan be an unsubstituted Cm alkoxy, and R^7a2 and R^7aa can be both hydrogen. In other embodiments. R^7alcan be a substituted Cm alkoxy, and R^7a2 and R^7a'’ can be both hydrogen. For example, R^7dlcan be a substituted Cm alkoxy substituted with an amino, mono-substituted amino or a di-substituted amino. In some embodiments. R^7al can be hydrogen, R^/a2 can be an optionally substituted Cm alkyl, and R^/a3 can be hydrogen. In other embodiments, R^7al can be hydrogen. R^7a2 can be a substituted C3.6 cycloalkvl. and R'^iL’ can be hydrogen. In still other embodiments, R^7al can be hydrogen. R'^a2 can be a mono-25WO 2015/026792

PCT/US2014/051642 substituted amino, and R^7d3 can be hydrogen. In yet still other embodiments, R^7al can be a mono-substituted amino or an optionally substituted O-amido (such as -C(=O)NH₂) and R'^a2and R^7aj can be both hydrogen. For example, the mono-substituted amino of R^7al or R^7a2 can be —N(C]_4 alkyl), such as -NCH3. In some embodiments, R^7al can be a substituted Ci_8 alkyl (such as an amino substituted Cm alkyl) and R^7a2 and R^7aj can be both hydrogen. In other embodiments, R^7al and R^7a2 can be both hydrogen and R^7aj can be halogen. In other embodiments, R^7dl and R^7d3 can be both hydrogen and R^7a2 can be an optionally substituted heterocyclyl, such as an optionally substituted mono-cyclic heterocyclyl. Examples of optionally substituted mono-cyclic heterocyclyl at R^7a2 include, but are not limited to, an optionally substituted azetidine, an optionally substituted pyrrolidine, an optionally substituted pyrrolidinone, an optionally substituted piperidine and an optionally substituted oxetane.

[0088] When R^7al. R^7d? and/or R^7dJ are substituted, possible substituent(s) includes those provided in the list of “substituted” along with urea, amidine and acetylurea. For example, the Cm alkyl, C₃.(, cycloalkyl and mono-cyclic heterocyclyl of R^7a2 can be substituted with various substituent(s), such as, halo, hydroxy, Cm alkoxy, an optionally substituted aryl(Ci_4 alkyl), an optionally substituted C-carboxy. amino, an optionally substituted mono-substituted amino, an optionally substituted di-substituted amino, an optionally substituted C-amido. an optionally substituted N-amido, an optionally substituted N-carbamyl, an optionally substituted N-sulfonamido, an optionally substituted urea, an optionally substituted amidine and an optionally substituted acetylurea (e.g.. halogenated acetylurea). Non-limiting examples of substituted Cm alkyls and substituted C3.6 cvcloalkyls of R^7a2 are as follows:

-(CH₂)-NH(=O)CH₃. -(CH₂)-NH₂.

. >ZWX jsjxrx

ox/vn.

jx/xrs |NH(CH₃)

vA/VX

NHBoc σννχ

σνυχ

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PCT/US2014/051642

Λωλ

. -(CH₂)-OH.

JA/VC jw·.

.ΛΛΛ

,ΛΛΛ

Formula (Ia3) κ/WX [0089]

In some embodiments. L of Formula (la) can be Formula (Ia3):

(Ia3)

WO 2015/026792

PCT/US2014/051642 wherein: the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted cycloalkyl an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R^8aj can be selected from hydrogen, halogen, hydroxy, an optionally substituted C|_s alkyl, an optionally substituted C2s alkenyl, an optionally substituted C'2-χ alkynyl. an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C|.r alkoxy, an optionally substituted alkoxyalky1, amino, mono-substituted amino, di-substituted amino. halo(Ci-8 alkyl), haloalkyl and an optionally substituted C-carboxy.

[0090] In some embodiments of Formula (la3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cvcloalkyl. In other embodiments of Formula (Ia3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered cvcloalkyl. In still other embodiments of Formula (la3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted and (for example, phenyl). In some embodiments of Formula (Ia3), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-mcmbered heteroaryl. In other embodiments of Formula (Ia3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroaryl. In still other embodiments of Formula (Ia3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl. In yet still other embodiments of Formula (la3). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6membered heterocyclyl.

[0091] In some embodiments, the bicyclic ring system can be selected from an (Fv/q optionally substituted . an optionally substituted

Ό

and an

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PCT/US2014/051642 wherein each optionally substituted

can be independently absent or a bond; each R^A?. each R^A6. each R^A' can be halogen, an unsubstituted C|._(l alkyl, hydroxy.

amino, an optionally substituted mono-substituted amino, an optionally substituted di substituted amino, -(CEEImOH, -(CEFImNEE or N-sulfmamido (for example, -NHS(=O)C]_4 alkyl), or two R^A\ two R^A6 or two R^A7 are taken together to form an optionally substituted 5- membered ring to an optionally substituted 6-membered ring (such as an optionally substituted cvcloalkyl or an optionally substituted heterocyclyl); and R^AS can be hydrogen or an unsubstituted C i.₆ alkyl. In some embodiments of this paragraph.......can be absent. In some embodiments of this paragraph,.....- can be a bond such that a double bond is present between the between carbons. In some embodiments, at least two R^A? groups can be an unsubstituted Ci.g alkyl (for example, CH3). In some embodiments, at least two R^A6groups can be an unsubstituted C|-6 alkyl (lor example, CH3). Examples of these bi-cyclic groups include the following:

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[0092] In some embodiments of Formulae (la), (Ial). (Ia2) and/or (Ia3). R^la can be hydrogen. In other embodiments of Formulae (la). (Ial). (Ia2) and/or (Ia3), R^ld can be an unsubstituted Cm alkyl.

[0093] In some embodiments of Formulae (la), (Ial), (Ia2) and/or (Ia3). both R^?aand R^2al can be hydrogen. In other embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3). R^2a can be hydrogen and R^2al can be an unsubstituted Cm alkyl. In still other embodiments of Formulae (la). (Ial ). (Ia2) and/or (la3). R^2a can be hydrogen and R^2al can be a substituted C|.4 alkyl. In yet still other embodiments of Formulae (la). (Ial). (Ia2) and/or (la3), R^2a can be hydrogen and R^2al can be an optionally substituted aryl(C|.6 alkyl) or an optionally substituted heterocyclyl(C|_6 alkyl). In some embodiments of Formulae (la), (lai). (Ia2) and/or (la3), R^2a can be hydrogen and R^2al can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3). R^2a can be hydrogen and R^2al can be hydroxy. In still other embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3). R^2al can be hydrogen, and R^la and R^2a can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl (for example, pyrrolidinyl) or an optionally substituted 6 membered heterocyclyl (for example, piperdinyl). In yet still other embodiments of Formulae (la), (Ial), (Ia2) and/or (Ia3). R^2a and R^2al both can be an optionally substituted Cm alkyl.

[0094] In some embodiments of Formulae (la), (lai). (Ta2) and/or (Ia3). R^3a can be hydrogen, and R'^al can be selected from amino, an unsubstituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3.6 cvcloalkyl (for example, cyclopropyl), an unsubstituted Cm alkoxy (such as OCH3). an unsubstituted -O

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PCT/US2014/051642 carboxy (such as -OC(=O)Cm alkyl), hydroxy, halogen, an unsubstituted heteroaryl (for example, thiazole) and an optionally substituted heterocyclyl (for example, azetidinc). In some embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3). R’^L1 can be hydrogen, and R^jalcan be hydroxy. In other embodiments or Formulae (la). (Ial). (Ia2) and/or (Ia3). R^3a and R^jal can be both halogen. In still other embodiments of Formulae (la). (Ial). (Ta2) and/or (Ia3), R^ia can be hydrogen, and R^jal can be unsubstituted Cm alkyl. In yet still other embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3), R^ad can be hydroxy, and R^3dl can be selected from amino, an unsubstituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynvl, an unsubstituted C3.6 cycloalkvl (for example, cvclopropyl), an unsubstituted Cm alkoxy (such as OCH3), hydroxy, halogen, an unsubstituted heteroaryl (for example, thiazole) and an optionally substituted heterocyclyl (for example, azetidine). In some embodiments of Formulae (la), (Ial), (Ia2) and/or (Ia3), R^ja can be hydroxy, and R'^ialcan be an unsubstituted Cm alkyl. In other embodiments of Formulae (la), (lai), (Ia2) and/or (la3), R^ja can be hydroxy, and R^,al can be an unsubstituted C₂_₄ alkenyl (such as ethenyl or propenyl) or an unsubstituted C₂_4 alkynyl (such as ethynyl or propynyl). In still other embodiments of Formulae (la), (Ial). (Ia2) and/or (Ia3), R^ja can be hydroxy, and R’^al can be CF3. In yet still other embodiments of Formulae (la), (Ial). (Ia2) and/or (Ia3). R^aa can be hydroxy, and R^3al can be CHF2. In some embodiments of Formulae (la). (Ial), (Ta2) and/or (Ia3), R'^a can be halogen, and R’^al can be CF3 or CHF2. In other embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3), R'^,a can be halogen, and R^jal can be CHF2. In some embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3), R^ad can be hydroxy, and R^3dl can be an unsubstituted C3.6 cycloalkyl, for example, an unsubstituted cyclopropyl. In some embodiments of Formulae (la), (Ial), (Ia2) and/or (Ia3), R^aa can be halogen, and R'^ial can be an unsubstituted C3.6 cycloalkyl, for example, an unsubstituted cyclopropyl. In other embodiments of Formulae (la), (Ial), (la2) and/or (la3). R'^,a can be an unsubstituted Cm alkoxy (such as methoxy), and R^aal can be an unsubstituted Cm alkyl (such as methyl). In still other embodiments of Formulae (la), (Ial ). (Ia2) and/or (la3). R’^,a and R^ial can be both an unsubstituted Cm alkyl, for example, R^ja and R^,al can be both methyl. In yet sill other embodiments of Formulae (la). (Ial), (la2) and/or (Ia3), one of It''¹ and R’^dl can be an optionally substituted mono-cyclic heteroaryl; and the other of R^3a and R^3al can be hydroxy.

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In some embodiments of Formulae (la), (lai), (Ia2) and/or (Ia3), one of R^ja and R^jal can be an unsubstituted Cm alkyl (such as methyl) ; and the other of R^3a and R’^al can be an unsubstituted -O-carboxy (such as -OC(=O)Cm alkyl).

[0095] When one of R’^a and R’^al is a substituted Cm alkyl, the Cm alkyl can be substituted with various substituents. For example, in some embodiments, one of R’^a and R^jal is a substituted Cm alkyl substituted with substituent selected from halogen, hydroxy, amino, mono-substituted amino (for example, -NH(Cm alkyl)), di-substituted amino, -Namido. mono-cyclic heteroaryl and mono-cyclic heterocyclyl. In some embodiments, one of R‘^,a and R^jal can be an optionally substituted mono-cyclic heteroaryl or an optionally substituted mono-cyclic heterocyclyl and the other of R^3a and R'^ial can be hydroxy. The mono-cyclic heteroaryl substituted on the Cm alkvl of one of R^3a and R'^,al can be 5membered or 6-membered heteroaryl. The mono-cyclic heterocyclyl substituted on the Cm alkyl of one of R^ia and R'^ial can be 4-membered. 5-membered or 6-membered heterocyclyl. For example, one of R^ja and R^jal can be a substituted Cm alkyl substituted with substituent selected from an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine, an optionally substituted morpholine, an optionally substituted triazole, an optionally substituted piperazinone and an optionally substituted azetidine.

[0096] In some embodiments of Formulae (la). (Ial). (Ia2) and/or (Ia3). R’^a and R’^al can together form N=OR^a. In some embodiments of Formulae (la), (lai). (Ia2) and/or (Ia3), R^ia and R’^al together form N=OH. In other embodiments of Formulae (la), (lai). (Ia2) and/or (Ia3), R'^,a and R^aal can together form N=OCH3. In some embodiments of Formulae (la). (Ial), (Ia2) and/or (Ia3), R'^,a and R'^ial can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring. In some embodiments of Formulae (la), (lai), (Ia2) and/or (Ia3), the 3 to 6 membered ring can be a C₃.6 cycloalkyl. In other embodiments of Formulae (la). (Ial). (Ia2) and/or (Ia3), the ring can be a 3 to 6 membered heterocyclyl. for example, an optionally substituted oxetane or an optionally substituted oxazolidinone. In some embodiments of Formulae (la), (lai). (Ia2) and/or (Ia3), the carbon to which R^ja and R’^dl are attached can be a chiral center. When the carbon to which IF'^a and R '^al are attached a chiral center, in some embodiments of Formulae (la), (lai),

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PCT/US2014/051642 (Ia2) and/or (Ia3). the carbon can have a (R)-configuration. In other embodiments of

Formulae (la), (lai), (Ia2) and/or (la3), the carbon to which R^ja and R^jal are attached can have a (S)-configuration.

Formula (lb) [0097]

In some embodiments, L of Formula (I) can be Formula (lb):

(lb).

wherein the dotted curved line between X^lb and X'^,b indicates a bi-cyclic ring selected from an optionally substituted bi-cyclic heteroaryl and an optionally substituted bi-cyclic heterocyclvl by joining X^lb and X^jb together, wherein--------between X^lb and X^2b represents a single or double bond between X^lb and X^2b;--------between X^2b and X'^lb represents a single or double bond between X^2b and X'^lb; wherein X^lb. X^2b and X'^,b can be each independently C (carbon). N (nitrogen), O (oxygen) or C(=O); and provided that at least one of X^lh, X^2b and X^jb comprises a nitrogen atom and both.......- cannot be double bonds; with the proviso that the valencies of X^lb. X^2b and X^jb can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted Cm alkyl: and X^lb, X^2b and X^3b are uncharged. In some embodiments, the valencies of X^lb. X^2b and X^jb can be each independently satisfied with a substituent selected from hydrogen and an unsubstituted Cm alkyl. In some embodiments, the valencies of X^lb, X^2b and X^3b can be each independently satisfied with hydrogen or methyl.

[0098] In some embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heteroaryl. In other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 9-membered bi-cyclic heterocvclyl. In still other embodiments of Formula (lb), the bi-cyclic ring can be an optionally substituted 10-membered bi-cyclic heteroaryl. In yet still some embodiments of Formula (lb), the bicyclic ring can be an optionally substituted 10-membered bi-cyclic heterocyclyl.

WO 2015/026792

PCT/US2014/051642 [0099] In some embodiments of Formula (lb), X^lb can be C, X^?b can be N and X^3b can be C. In other embodiments of Formula (lb), X^lb can be N, X^2b can be N and X^3b can be

C. In still other embodiments of Formula (lb), X^lb can be N, X^2b can be C(=O) and X^jb can be N. In yet still other embodiments of Formula (lb), X^lb can be C, X^2b can be O and X^jb can beC.

[0100] In some embodiments of Formula (lb), when X^lb can be C, X^2b can be N and X'^,b can be C, the bi-cyelic ring can be an optionally substituted bi-cyclic heteroaryl ring. In other embodiments of Formula (lb), when X^lb can be C, X^2b can be N and X^3b can be C. the bi-cyclic ring can be an optionally substituted bi-cyclic heterocyclyl ring.

Formula (Ibl) [0101] In some embodiments. L of Formula (lb) can be Formula (Ibl):

R^1b O

(Ibl) wherein: the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R^4b3 can be selected from hydrogen, halogen, hydroxy, an optionally substituted Ci_s alkyl, an optionally substituted C₂. 8 alkenyl, an optionally substituted C₂.g alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C|_s alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino. halo(C|-s alkyl), haloalkyl and an optionally substituted C-carboxy.

[0102] In some embodiments of Formula (Ibl), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered cvcloalkenyl. In other embodiments of Formula (Ibl), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered

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PCT/US2014/051642 cvcloalkenyl. In still other embodiments of Formula (Ibl). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted ary l (for example, phenyl). Tn some embodiments of Formula (Ibl). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heteroaryl. In other embodiments of Formula (Ibl), the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6-membered heteroaryl. In still other embodiments of Formula (Ibl). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 5-membered heterocyclyl. In yet still other embodiments of Formula (Ibl). the dashed semi-circle along with the two carbon atoms to which it is connected can form an optionally substituted 6membered heterocyclyl.

|0103] In some embodiments, the bi-cyclic ring system can be selected from optionally substituted

, an optionally substituted an

optionally substituted an optionally substituted

and an optionally

N(R^B4) ; wherein each-----can be independently absent or a bond;

(R^B3)o-4 substituted each R^BI, each R^li2 and each R^Bl can be an unsubstituted C i_6 alkyl, halogen, hydroxy, amino, mono-substituted amino, di-substituted amino or -NH-S(=O)Cm alkyl; and R^B4 can be hydrogen or an unsubstituted C i_6 alkyl,. In some embodiments of this paragraph.......can be absent. In some embodiments of this paragraph.......can be a bond such that a double bond is present between the between carbons. In some embodiments, at least two R^B2 groups can be an unsubstituted C i alkyl (for example, CH3). In some embodiments, at least two

WO 2015/026792

PCT/US2014/051642

R^Bj groups can be an unsubstituted Cm alkyl (for example, CII3). Examples of these bicyclic groups include the following:

[0104] In some embodiments of Formulae (lb) and (Tbl), R^lb can be hydrogen.

[0105] In some embodiments of Formulae (lb) and (Ibl), both R^?b and R^?bl can be hydrogen. In other embodiments of Formulae (lb) and (Tbl), R^2b can be hydrogen and R^2blcan be an unsubstituted Cm alkyl. Tn still other embodiments of Formulae (lb) and (Tbl), R^2bcan be hydrogen and R^2bl can be a substituted Cm alkyl. In yet still other embodiments of Formulae (lb) and (Ibl), R^2b can be hydrogen and R^2bl can be an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclvl(C|_6 alkyl). In some embodiments of Formulae (lb) and (Ibl). R^2b can be hydrogen and R^2bl can be an alkoxvalkyl. an aminoalkyl or a hydroxvalkyl. In other embodiments of Formulae (lb) and (Ibl), R^2b can be hydrogen and R^2bl can be hydroxy. In still other embodiments of Formulae (lb) and (Ibl), R^2bl can be

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PCT/US2014/051642 hydrogen, and R^lb and R^2b can be joined together with the atoms to which they are attached to form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.

Formula (Ic) [0106] In some embodiments, L can be Formula (Ic):

R^1c R^3cI p2c1 I p3c1

R^5c (Ic).

[0107] In some embodiments of Formula (Ic), R^lc can be hydrogen. In other embodiments of Formula (Ic), R^lc can be an unsubstituted Cm alkyl.

[0108] In some embodiments of Formula (Ic), both R^2t and R^2d can be hydrogen. In other embodiments of Formula (Ic), R^2t can be hydrogen and R^2d can be an unsubstituted Cm alkyl. In still other embodiments of Formula (le), R^2c can be hydrogen and R^2tl can be a substituted Cm alkyl. In yet still other embodiments of Formula (Ic). IC can be hydrogen and R^2d can be an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(C|.6 alkyl). In some embodiments of Formula (Ic), R^2t can be hydrogen and R^2dcan be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formula (Ic), R^2t can be hydrogen and R^2d can be hydroxy. In still other embodiments of Formula (Ic), R^2t and R^2d both can be an optionally substituted Cm alkyl.

[0109] In some embodiments of Formula (Ic), R^Jt can be hydrogen, and R’^d can be selected from amino, an unsubstituted Cm alkyl, an unsubstituted C?-4 alkenyl, an unsubstituted C?_4 alkynyl. an unsubstituted C3.6 cycloalkyl (for example, cyclopropyl), an unsubstituted Cm alkoxy (such as OCH3), hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole). In some embodiments, R’^c can be hydrogen, and R^jd can be hydroxy. In other embodiments. R^JC and R’^d can be both halogen. In still other embodiments, R^JC can be hydrogen, and R^jd can be unsubstituted Cm alkyl. In yet still other embodiments of Formula (Ic). R^Jt can be hydroxy, and R^jd can be selected from amino, an unsubstituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an

-37·

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PCT/US2014/051642 unsubstituted C3.6 cycloalkyl (for example, cyclopropyl), an unsubstituted Cm alkoxy (such as OCH3), hydroxy, halogen and an unsubstituted heteroaryl (for example, thiazole). In some embodiments of Formula (Ic). R^Jt can be hydroxy, and R^Jtl can be an unsubstituted Cm alkyl. In some embodiments of Formula (Ic). R’^c and R^Jtl can together form N=OR^C. for example, N=OH or N=OCH₃. In some embodiments of Formula (Ic). R^JC and R^?cl can join together with the atom to which they are attached to form an optionally substituted 3 to 6 membered ring. In some embodiments, the 3 to 6 membered ring can be a C3.6 cycloalkyl. In other embodiments, the ring can be a 3 to 6 membered heterocyclyl. for example, an optionally substituted oxetane. In some embodiments, the carbon to which and R'^iel are attached can be a chiral center. When the carbon to which R^3e and R^{3t 1} are attached a chiral center, in some embodiments, the carbon can have a (R)-contiguration. In other embodiments, the carbon to which R^Jt and R^3tl are attached can have a (S)-configuration.

[0110] In some embodiments of Formula (Ic), Zf can be N. In some embodiments of Formula (Ic), Z? can be CH.

[0111] In some embodiments of Formula (Ic), R^4c and R^?c can be taken together to form an unsubstituted aryl (for example, phenyl). In other embodiments of Formula (Ic), R^4c and R^?t can be taken together to form an unsubstituted heteroaryl, such as piperdinyl. In still other embodiments of Formula (Ic), R^4t and R^?t can be taken together to form an optionally substituted heterocyclyl. In some embodiments, the optionally substituted heterocyclyl can be an optionally substituted tricyclic heterocyclyl, such as an optionally *1 I * -s' substituted. θ wherein * each indicate a point of attachment to the 6-membered ring.

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Formula (Id) [0112] In some embodiments, L can be Formula (Id): R^1d

[0113] In some embodiments of Formula (Id), R^ld can be hydrogen. In other embodiments of Formula (Id ). R^ld can be an unsubstituted C 1.4 alkyl.

[0114] In some embodiments of Formula (Id), both R^?d and R^2dl can be hydrogen. In other embodiments of Formula (Id), R^2d can be hydrogen and R^2dl can be an unsubstituted C1.4 alkyl. In still other embodiments of Formula (Id), R^2d can be hydrogen and R^2dl can be a substituted Cm alkyl. In yet still other embodiments of Formula (Id), R^2d can be hydrogen and R^2dl can be an optionally substituted aryl(Ci_6 alkyl) or an optionally substituted hctcrocyclyl(Ci_6 alkyl). In some embodiments of Formula (Id), R^2d can be hydrogen and R^2dl can be an alkoxyalkyl, an aminoalkyl or a hydroxyalkyl. In other embodiments of Formula (Id). R^2d can be hydrogen and R^2dl can be hydroxy. In still other embodiments of Formula (Id), R^2d and R^2dl both can be an optionally substituted Cm alkyl.

[0115] In some embodiments of Formula (Id), m^d can be 0. In other embodiments of Formula (Id). m^d can be 1.

[0116] In some substituted C5 cycloalkyl.

In some embodiments of Formula (Id), ring B^d can be an optionally In some embodiments, ring B^d can be an optionally substituted embodiments of Formula (Id), ring B^dl can be an optionally substituted pyridinvl having the structure

The C5 cycloalkyl and/or pyridinyl ring can be unsubstituted or substituted with one or more substituents. Suitable substituents include, but are not limited to, amino, mono-substituted amino, di-substituted amino, hydroxyalkyl, alkyl and alkoxy.

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PCT/US2014/051642 [0118] In some embodiments, A can be substituted. In other embodiments, A can be unsubstituted. When A is substituted, possible substituent(s) includes those provided in the list of “substituted along with those described herein.

[0119] In some embodiments, A can be an optionally substituted aryl. For example, A can be an optionally substituted phenyl. In some embodiments, A can be a parasubstituted phenyl, a meta-substituted phenyl or an ortho-substituted phenyl. In some embodiments, A can be a di-substituted phenyl. For example. A can be a 3,4-substituted

. In some embodiments. A can be a substituted phenyl that is substituted with 3 more substituents. In other embodiments, A can be unsubstituted phenyl.

In some embodiments, A can be an optionally substituted naphthyl.

[0120] In some embodiments and without limitation. A can be a phenyl substituted with one or more substituents selected from an unsubstituted Cm alkyl, an optionally substituted Cm alkyl, cycloalkyl, hydroxy, an optionally substituted Cm alkoxy, Cm alkoxy, halogen, haloalkyl. an optionally substituted haloalkoxy, nitro, amino, monosubstituted amino, di-substituted amino. -O-amido. sulfenyl, alkyoxyalkyl. an optionally substituted aryl (for example, an optionally substituted phenyl), an optionally substituted monocyclic heteroaryl. an optionally substituted monocyclic heterocyclyl, an optionally substituted aryl(Ci_4 alkyl), an optionally substituted monocyclic heteroaryl(C|_4 alkyl), an optionally substituted monocyclic heterocyclyl(C m alkyl), hydroxyalkyl and aminoalkyl. In some embodiments, the optionally substituted Cm alkoxy can be further substituted, for example, further substituted with a substituent selected from Cm alkyl, halo, hydroxy, Ccarboxy, C-amido. amino, mono-alkyl amine, di-alkyl amine and an amino acid. In some embodiments, the optionally substituted haloalkoxy can be further substituted, for example.

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PCT/US2014/051642 further substituted with an Cm alkoxy. In some embodiments, the optionally substituted heteroaryl can be further substituted, for example, further substituted with an Cm alkyl.

[0121] Examples of suitable substituents include, but are not limited to, methyl, ethyl, propyl (n-propyl and iso-propyl), butyl (n-butyl, iso-butyl and t-butyl). hydroxy, methoxy, ethoxy, propoxy (n-propoxy and iso-propoxy), butoxy (n-butoxy, iso-butoxy and tbutoxy). phenoxy. bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy, trifluoromethoxy. cyano, N,N-di-methyl-amine, N.N-di-ethyl-amine, N-methyl-N-ethyl-amine, N-methylamino. N-ethyl-amino, amino, N-amido (for example, -NH-C(=O)Cm alkyl), alkylthio (such as CH3CH2S-), N-sulfonamido (for example, -NH-S(O)₂Cm alkvl), an optionally substituted phenyl, an optionally substituted imidazole, an optionally substituted morpholinyl, an optionally substituted pyrazole, an optionally substituted pyrrolidinyl. an optionally substituted pyridinyl, an optionally substituted piperidinyl, an optionally substituted piperidinone, an optionally substituted pyrrolidinone, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1,2,4-oxadiazole, -(CH₂)m-0H, (CH?)i-2-NH(CH3), an optionally substituted -(CtDi-a-imidazole, an optionally substituted (CH2)i_2-pyrrolidinone, an optionally substituted -(CH₂)|.₂-imidazolidinone. -O(CH₂)₂-NH₂, O(CH₂)₂-NH(CH₃), -O(CH₂)₂-N(CH₃)₂, -O-(CH₂)₂.₄OH, -O(CH₂)₂OCH₃. an optionally substituted -0(CH₂)o-₂-cyelopentanone. an optionally substituted -0(CH₂)o-₂pynOlidinone. an optionally substituted -0(CH₂)o-₂-morpholinyl. an optionally substituted -0(CH₂)o_₂-triazole. an optionally substituted -0(CH₂)o_₂-imidazole, an optionally substituted -0(CH₂)o_₂pyrazole, an optionally substituted -0(CH₂)o_₂-tetrahydrofuran, an optionally substituted 0(CH₂)o-2-pyrrolidinone, an optionally substituted -0(CH₂)o_₂-tetrazole, an optionally substituted -0(CH2)o-₂-tetrazolone,

F-

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PCT/US2014/051642

Ο

+-¼

[0122] In some embodiments, A can be an optionally substituted cvcloalkyl. Suitable examples ol' optionally substituted cycloalkyls include, but are not limited to, an optionally substituted cyclohexvl and an optionally substituted cycloheptyl. In other embodiments, A can be an optionally substituted cycloalkenyl, for example, an optionally substituted cyclohexenvl. In some embodiments, A can be an optionally substituted bi-cyclic cycloalkenyl, such as

[0123] In some embodiments, A can be an optionally substituted aryl(C|_2 alkyl).

In some embodiments. A can be an optionally substituted benzyl.

[0124] In some embodiments. A can be an optionally substituted mono-cyclic heteroaryl. In some embodiments. A can be an optionally substituted mono-cyclic 5membered heteroaryl. In other embodiments, A can be an optionally substituted mono-cyclic 6-membered heteroaryl. In some embodiments. A can be an optionally substituted bi-cyclic heteroaryl.

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PCT/US2014/051642 [0125] In some embodiments, the optionally substituted heteroaryl can be selected from an optionally substituted imidazole, an optionally substituted thiazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyridine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted quinoline, an optionally substituted imidazole, an optionally substituted oxazole, an optionally substituted isoxazole, an optionally substituted benzoimidazole, an optionally substituted benzooxazole, an optionally substituted benzothiazole and an optionally substituted imidazo[l,2-a]pyrimidine. In some embodiments, A can be an optionally substituted thiophene. In other embodiments, A can be an optionally substituted thiazole. In still other embodiments, A can be an optionally substituted pyridine. In yet still other embodiments, A can be an optionally substituted pyrimidine. In some embodiments, A can be an optionally substituted pyrazine. In other embodiments, A can be an optionally⁷ substituted imidazole. In still other embodiments, A can be an optionally substituted benzoimidazole, an optionally substituted benzooxazole or an optionally substituted benzothiazole.

[0126] In some embodiments, A can be an optionally substituted heterocyclyl, for example, an optionally substituted mono-cyclic heterocyclyl or an optionally substituted bicyclic heterocyclyl. In some embodiments, A can be an optionally substituted .0

O . In other embodiments, A can be an optionally substituted

In still other embodiments, A can be an optionally substituted . In yet still other embodiments. A can be an optionally substituted h

In some embodiments. A can be an optionally substituted

. In other embodiments, A

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PCT/US2014/051642 can be an optionally substituted

In still other embodiments. A can be an optionally substituted optionally substituted

In yet still other embodiments. A can be an

In some embodiments. A can be an optionally substituted

[0127] In some embodiments, A can be substituted with one or more R^A,s. In some embodiments, one R^A can be present. In some embodiments, two R^A‘s can be present. In some embodiments, three R^A’s can be present. In some embodiments, four or more R^A,s can be present. When two or more R^A's are present, two or more R^A,s can be the same or two or more R^A,s can be different. In some embodiments, at least two R^vs can be the same.

In some embodiments, at least two R^A's can be different. In some embodiments, all the R^A,s can be the same. In other embodiments, all the R^A,s can be different. In some embodiments.

A can have one of the following structures:

[0128] In some embodiments, R^A can be each independently selected from an unsubstituted C|-4 alkyl, an optionally substituted C|_4 alkyl, cycloalkyl, hydroxy, an optionally substituted C|_4 alkoxy, C|_4 alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono-substituted amino, di-substituted amine, sulfenyl, alkyoxyalkyl, aryl, monocyclic heteroaryl, monocyclic heterocyclyl and aminoalkyl. In some

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PCT/US2014/051642 embodiments, the optionally substituted Cm alkoxy can be further substituted, for example, further substituted with a substituent selected from Cm alkyl, halo, hydroxy, C-carboxy, Camido. N-amido, amino, mono-alkyl amine, di-alkyl amine and an amino acid. In some embodiments, the optionally substituted haloalkoxy can be further substituted, for example, further substituted with an Cm alkoxy. In some embodiments, the optionally substituted heteroaryl can be further substituted, for example, further substituted with an Cm alkyl.

[0129] In some embodiments, each R^A can be an alkyl, such as methyl, ethyl, propyl (n-propyl and iso-propyl) and/or butyl (n-butyl. iso-butyl and t-butyl).

[0130] In some embodiments, each R^A can be an optionally substituted alkoxy, for example, methoxy, ethoxy, propoxy (n-propoxy and iso-propoxy). butoxy (n-butoxy. isobutoxv and t-butoxy), phenoxy, -O(CH2)2-NH₂, -O(CH₂)₂-NH(CH3). -O(CH₂)₂-N(CH3)₂, -O-

an optionally substituted -0(CH2)o-2-morpholinyl, an optionally substituted -0(CH₂)o_₂triazole, an optionally substituted -0(CH2)o-2-imidazole, an optionally substituted -0(CH₂)o_₂-45WO 2015/026792

PCT/US2014/051642 cvclopentanone, an optionally substituted -0(CH2)o-2PyiTolidinone, an optionally substituted 0(CH2)o-2-pvrazole, an optionally substituted -0(CH2)o-2-tetrahydrofuran. an optionally substituted -0(CH2)o-2-pyirolidinone, an optionally substituted -0(CH2)o_2-tetrazole. an £^OV A optionally substituted -0(CH2)o-2-tetrazolone and/or V . In some embodiments, R can be substituted Cu, alkoxy substituted by one or more of the following: halo, hydroxy. C i_ alkyl, cyano, amino, mono-substituted amino, di-substituted amino, sulfonaniidocarbonyl, hydroxamidine. C-amido. acyl, C-carboxy. O-carboxy, sulfonyl, S-sulfonamido. O-linked amino acid and carbonate ester.

[0131] trilluoromethyl.

In some embodiments, each R^A can be haloalkyl. for example, [0132]

In some embodiments, each R^A can be an optionally substituted

F haloalkoxy, for example, difluoromethoxy, trifluoromethoxy, _F^°y pK⁰'/. H,cA°y _{and/or F}£°y [0133] In some embodiments, each R^A can be halogen, for example, chloro.

bromo and/or fluoro.

[0134] In some embodiments, each R^A can be amino, a mono-substituted amine or a di-substituted amine. For examples. R^A can be N,N-di-methyl-amine. N,N-di-ethyl-amine. N-methyl-N-ethyl-amine. N-methyl-amino, N-ethyl-amino and/or amino.

10135] In some embodiments, each R^A can be hydroxy.

[0136] In some embodiments, each R^A can be alkylthio, for example ethylthio.

[0137] In some embodiments, each R^A can be aminoalkyl, such as -(Ctl2)i-2NH(CH₃).

[0138] In some embodiments, each R^A can be alkoxyalkvl. for example, -CH2-OCH₃.

[0139] In some embodiments, each R^A can be an optionally substituted aryl(C|.4 alkyl). In some embodiments, each R^A can be an optionally substituted monocyclic heteroaryl(Ci_4 alkyl). In some embodiments, each R^A can be an optionally substituted

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PCT/US2014/051642 monocyclic heterocyclyl(Ci_4 alkyl). Non-limiting examples include an optionally substituted

-(CHif-s-imidazole, an optionally substituted -(CFFh-s-pynOlidinonc. an optionally substituted -(CH?)i-2-imidazolidinone.

[0140] In some embodiments, each R^A can be hvdroxyalkyl. for example. -(CH₂)i4-OH.

[0141]

In some embodiments, each R^A can be -O-amido, for example, ^H2^N

H N [0142] In some embodiments, each R^A can be -N -amido, for example, O . [0143] In some embodiments, each R^A can be -N-sulfonamido, for example, [0144] In some embodiments, each R^A can be aminoalkyl, for example, -CFLNH₂ and/or -CH₂-N(CH₃)H.

[0145] In some embodiments, each R^A can be an optionally substituted aryl, for example, an optionally substituted phenyl.

[0146] In some embodiments, each R^A can be an optionally substituted monocyclic heteroarvl. such as an optionally substituted imidazole, an optionally substituted pyrazole. an optionally substituted pyridinyl, an optionally substituted pyrimidine, an optionally substituted pyrazine and/or an optionally substituted 1,2,4-oxadiazole.

[0147] In some embodiments, each R^A can be an optionally substituted monocyclic heterocyclyl, for example, an optionally substituted pyrrolidinyl, an optionally substituted piperidinyl, an optionally substituted morpholinyl and/or an optionally substituted pyrrolidinonc.

[0148] In some embodiments, Y can be an optionally substituted aryl. In some embodiments, Y can be a para-substituted phenyl, a meta-substituted phenyl or an orthosubstituted phenyl. In some embodiments. Y can be a mono-substituted phenyl, such as a mono-halo substituted phenyl. Tn some embodiments. Y can be a di-substituted phenyl, for example a di-halo substituted phenyl. For example, mono-halo substituted phenyls and di-47WO 2015/026792

PCT/US2014/051642 halo substituted phenyls include, but are not limited to.

In some embodiments, Y can be di-substituted

phenyl of the structure F . In some embodiments. Y can be a substituted phenyl that is substituted with 3 more substituents. In other embodiments, Y can be unsubstituted phenyl. In some embodiments, Y can be a substituted naphthyl. In other embodiments. Y can be an unsubstituted naphthyl.

[0149] In some embodiments. Y can be an optionally substituted cycloalkyl (e.g., an optionally substituted cyclohexvl and an optionally substituted cycloheptyl). In other embodiments, Y can be an optionally substituted cycloalkenyl, for example, an optionally substituted cyclohexenyl. In some embodiments, Y can be an optionally substituted bi-cyclic cycloalkenyl, such as

[0150] In some embodiments. Y can be an optionally substituted mono-cyclic heteroarvl. In some embodiments, Y can be selected from an optionally substituted imidazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted pyridine, an optionally substituted pyrazole. an optionally substituted oxazole and an optionally substituted isoxazole. In some embodiments, Y can be a substituted mono-cyclic heteroaryl, including those described herein. In some embodiments. Y can be an unsubstituted mono-cyclic heteroaryl, including those described herein.

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PCT/US2014/051642 [0151] In some embodiments, Y can be an optionally substituted bi-cyclic heteroaryl. In some embodiments, Y can be selected from an optionally substituted benzothiophene, an optionally substituted benzofuran, an optionally substituted indole, an optionally substituted quinoline, an optionally substituted isoquinoline, an optionally substituted benzooxazole, an optionally substituted benzoisoxazole. an optionally substituted benzoisothiazole, an optionally substituted benzothiazole, an optionally substituted benzoimidazole, an optionally⁷ substituted benzotriazole, an optionally substituted 1Hindazole and an optionally substituted 2H-indazole. In some embodiments, Y can be selected

, an optionally substituted

from an optionally substituted

a substituted bi-cyclic heteroary l, including those described herein. In some embodiments. Y can be an unsubstituted bi-cyclic heteroaryl, including those described herein.

[0152] In some embodiments. Y can be an optionally substituted heterocyclyl. In some embodiments. Y can be an optionally substituted mono-cyclic heterocyclyl. such as an optionally substituted pyridinone. In other embodiment, Y can be an optionally substituted

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PCT/US2014/051642

. an bi-cvclic heterocyclyl. For example. Y can be an optionally substituted

optionally substituted or an optionally substituted [0153] When Y is substituted, Y can be substituted with one or more R^B's. In some embodiments, each R^B can be independently selected from cyano, halogen, an optionally substituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl. an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroarvl. an optionally substituted 5 or 6 membered heterocyclyl, hydroxy, Cm alkoxy, alkoxyalkyl, Cm haloalkyl. haloalkoxy, an unsubstituted acyl, an optionally substituted -C-carboxy, an optionally substituted -C-amido, sulfonyl, carbonyl, amino, mono-substituted amine, disubstituted amine and

O

[0154] In some embodiments, when Y is an optionally substituted phenyl, the phenyl can be substituted 1, 2, 3 or more times with cyano, halogen, an optionally substituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 5 or 6 membered heterocyclyl. hydroxy. Cm alkoxy, Cm haloalky l (such as CF3. CHF2), haloalkoxy (such as OCF3), an unsubstituted acyl, an optionally substituted -Ccarboxy, an optionally substituted-C-amido. sulfonyl, amino, mono-CM alkyl amine, di-Ci.4 alkyl amine and/or ” W . In other embodiments, when Y is an optionally substituted mono-cyclic heteroaryl, the mono-cyclic heteroaryl can be substituted 1, 2, 3 or more times with halo, an optionally substituted Cm alkyl, an optionally⁷ substituted phenyl and/or an unsubstituted acyl. In still other embodiments, when Y is an optionally substituted bi-cyclic

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PCT/US2014/051642 heteroaryl, the bi-cyclic heteroaryl can be substituted 1, 2, 3 or more times with halo, an optionally substituted Cm alkyl, an optionally substituted phenyl, hydroxy, Cm alkoxy, an unsubstituted acyl, carbonyl, cyano, amino, mono-CM alkyl amine and/or di-Ci_4 alkyl amine.

[0155] In some embodiments, Y can be an optionally substituted benzothiophene. In some embodiments, Y can be a substituted benzothiophene. In other embodiments, Y can be an unsubstituted benzothiophene. In some embodiments, the benzothiophene can be substituted with one or more of the following: halogen (such as fluoro, chloro and/or bromo), carbonyl. Cm alkyl, hydroxy. Cm alkoxy, NH/, and/or mono-substituted amine. For example, the benzothiophene can

. an optionally substituted be an optionally substituted . such as an

[0156] In some embodiments, Y can be an optionally substituted benzofuran.

[0157] In some embodiments, Y can be an optionally substituted indole. In some embodiments, Y can be a substituted indole. In some embodiments, the indole can be substituted 1. 2, 3 or more time with phenyl (substituted or unsubstituted). Cm alkyl and/or halo. In other embodiments. Y can be an unsubstituted indole.

[0158] In some embodiments, Y can be substituted with one or more halogen. In some embodiments, Y can be substituted with one or more unsubstituted Cm alkyl. In some embodiments, Y can be substituted with more or more hydroxy. In some embodiments, Y can be substituted with one or more optionally substituted phenyl. In some embodiments. Y can be substituted with one or more alkoxy. In some embodiments. Y can be substituted with

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PCT/US2014/051642 one or more acyl. In some embodiments, Y can be substituted with one or more amino, mono-substituted amino, or di-substitutcd amino. In some embodiments, Y can be substituted with one or more haloalky 1. In some embodiments, Y can be substituted with one or more haloalkoxv. In some embodiments, Y can be substituted with one or more Ccarboxy. In some embodiments. Y can be substituted with one or more C-amido. In some embodiments, Y can be substituted with one or more hydroxyalkyl.

[0159] In some embodiments, a compound of Formula (I) can be selected from the following compounds: 1, 13-1, 100. 101, 102. 103. 105, 106. 107, 108, 109. 110, 111. 112, 113. 114, 115. 116, 116a, 116b, 117. 117a, 117b, 118, 118a. 118b, 119, 120, 120a. 120 b. 121, 122, 122a. 122b, 123, 124. 125, 126, 127, 128, 129, 131, 132, 133, 134, 138, 139, 142. 143, 144. 145, 146, 147. 148. 151. 152, 153, 154, 155, 158. 159. 162. 163, 164. 165,

166. 167, 168. 169, 170, 171. 172. 173. 174, 175, 176, 177, 178. 179. 180. 181, 182. 183,

184. 185, 186. 187, 188, 189. 190. 191. 192, 193, 194, 195, 196. 197. 198. 199, 200. 201,

202. 203, 204. 205, 206, 207. 208. 209, 210, 211, 212, 213, 214. 215. 216. 218. 219, 221,

223, 224, 225. 226, 227, 228, 230, 231. 232, 233, 234, 235, 236. 237, 238, 239, 240. 241,

242. 243, 244, 245, 246, 247. 248. 249. 250, 251, 252, 253, 254. 255. 256. 257. 258. 259,

260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277,

278, 279. 280, 281. 282. 283, 284, 285, 286, 288. 289. 290. 291, 292, 293, 294, 295, 296.

297, 298. 299, 300. 301. 306, 307, 308, 309, 310. 312. 313. 314, 315, 316, 317, 318, 319.

357, 358. 359, 360, 361. 362, 363, 364, 365. 366. 367. 368, 369. 370, 371, 372, 373, 374.

393, 394. 395, 396, 397. 398, 399, 400, 402. 403. 404. 405. 406, 407, 408, 409, 410, 411.

412. 413, 414. 415, 416, 417. 418. 419. 420, 421, 422, 423, 424. 425. 426. 427, 428.429,

430. 431, 432. 433, 434, 435. 436. 437. 438, 439, 440, 441, 442. 443. 444. 445, 446.447,

448. 449, 450. 451, 452, 453. 454. 455. 456, 457, 458, 459, 460. 461. 462. 463, 464.465,

466. 467, 468. 469, 470, 471. 472. 475. 476, 477, 478, 479, 480. 481. 482. 483, 484.485,

486, 487, 488, 489, 490, 491, 492, 493, 494, 495, 496, 497, 498a, 498b, 498c, 498d, 499,

500, 501, 502, 503, 504, 505, 506, 507, 508, 509, 510, 511, 512, 513, 514, 515. 516, 517,

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PCT/US2014/051642

518, 519, 520, 521, 522, 523, 524, 525, 526, 527, 528, 529, 530, 531, 532, 533. 534,535,

536, 537, 538, 539, 540, 541, 542, 543, 544, 545, 546, 547, 548, 549, 550, 551, 552,553,

554, 555. 556, 557, 558. 559, 560, 561, 562, 563. 564. 565, 567, 568, 569, 570, 571.572.

573, 574. 575, 576, 577. 578, 579, 580, 581, 582. 583. 584. 585, 586, 587, 588, 589,590.

591, 592, 593, 594, 595. 596. 597. 598. 599, 600, 601, 602, 603. 604a. 604b. 604c. 604d. 605a, 605b, 605c, 605d, 606, 607, 608, 609, 610, 611, 612. 613, 614, 615, 616, 617, 618, 619, 620. 621, 622, 623a, 623b, 624a, 624b. 625. 626, 627, 628. 629, 630. 631, 632, 633a. 633b. 634. 635. 636, 637, 638, 639, 640. 641. 642, 643. 644. 645, 646, 647. 648, 649, 650. 651, 652. 653, 654, 655. 656, 657, 658, 659. 660. 661. 662. 663, 664, 665, 666, 667, 668. 669, 670, 671, 672, 673, 674, 675, 676, 677, 678, 680, 681 and 682, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I) can be selected from: 149. 150. 156. 157, 160. 217, 220, 222. 229, 287. 302. 303, 304. 305, 311, 401. 473 and 474. or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (1) can be selected from: 130, 135, 140 and 141, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I) can be 104 or 161, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I) can be 136 or 137, or a pharmaceutically acceptable salt of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in PCT Publication WO 2014/031784, published February 27. 2014.

Pharmaceutical Compositions [0160] Some embodiments described herein relate to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0161] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or

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PCT/US2014/051642 organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, cthancsulfonic acid, p-toluencsulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.

[0162] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound nor cause appreciable damage or injury to an animal to which delivery of the composition is intended.

[0163] As used herein, a carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues, for example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.

[0164] As used herein, a diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.

[0165] As used herein, an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A diluent” is a type of excipient.

[0166] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

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PCT/US2014/051642 [0167] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0168] Multiple techniques of administering a compound exist in the art including, but not limited to. oral, rectal, pulmonary, topical, aerosol, injection and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0169] One may also administer the compound in a local rather than systemic manner, for example, via injection or implantation of the compound directly into the affected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.

[0170] The compositions may. if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use. or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary⁷ administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

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PCT/US2014/051642

Methods of Use [0171] Some embodiments described herein relate to a method for ameliorating, treating and/or preventing a paramyxovirus viral infection, which can comprise administering an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0172] Some embodiments described herein relate to a method for inhibiting viral replication of a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0173] Some embodiments described herein relate to a method for contacting a cell infected with a paramyxovirus, which can comprise contacting a cell infected with the virus with an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof).

[0174] In some embodiments, the paramyxovirus infection is a human respiratory syncytial virus infection.

[0175] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, one or more compounds of Formula (T), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a respiratory⁷ syncytial viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used

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PCT/US2014/051642 to prevent a respiratory syncytial viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a respiratory syncytial virus. Tn some embodiments, an effective amount of one or more compounds of Formula (T). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the RSV polymerase complex. In some embodiments, the RSV can be RSV A. In some embodiments, the RSV can be RSV B.

[0176] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a hendravirus and/or nipahvirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the hendravirus polymerase complex and/or nipahvirus polymerase complex.

[0177] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical

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PCT/US2014/051642 composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a measles virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the measles polymerase complex.

[0178] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate mumps. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent mumps. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a mumps virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a

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PCT/US2014/051642 pharmaceutically acceptable salt thereof) can be used to inhibit the mumps polymerase complex.

[0179] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication a sendai virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the sendai virus polymerase complex.

[0180] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a HPIV-1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a HPIV-1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds

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PCT/US2014/051642 described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a HPIV-1 and/or HPIV-3. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the HPIV-1 polymerase complex and/or HPIV-3 polymerase complex.

[0181] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a HP1V-2 infection and/or HPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used to prevent a HPIV-2 infection and/or HPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a HPIV-2 and/or HPIV-4. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the HPIV-2 polymerase complex and/or HP1V-4 polymerase complex.

[0182] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to treat and/or ameliorate a human metapneumoviral infection. In some embodiments, an effective amount

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PCT/US2014/051642 of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a human metapneumoviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to inhibit the replication of a human metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used to inhibit the human metapneumovirus polymerase complex.

[0183] In some embodiments, an effective amount of one or more compounds of Formula (1). or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (1). or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate a lower respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus. a pneumovirus, and a metapneumovirus (such as those described herein).

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PCT/US2014/051642 [0184] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate a lower respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by RSV infection, measles, mumps, parainfluenza infection, and/or metapneumovirus (such as those described herein).

[0185] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate pneumonia due to a RSV infection and/or human parainfluenza virus 3 (HPIV-3) infection, in some embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of

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Formula (I), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate croup due to a RSV infection and/or human parainfluenza virus 1 (HPIV-1) infection.

[0186] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g.. a compound of Formula (I), or a pharmaceutically-' acceptable salt thereof) can be used treat and/or ameliorate due to fever, cough, runny- nose, red eyes, a generalized rash, pneumonia, an ear infection and/or bronchitis due to measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically⁷ acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (1), or a pharmaceutically acceptable salt thereof) can be used treat and/or ameliorate due to swelling of the salivary⁷ glands, fever, loss of appetite and/or fatigue due to mumps.

[0187] In some embodiments, an effective amount of one or more compounds of Formula (1), or a pharmaceutically acceptable salt thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be used to prevent a human parainfluenza viral infection. In some embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 1 (HPIV-1). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 2 (HPIV-2). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 3 (HPIV-3). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 4 (HPIV-4). In some embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat and/or ameliorate one or more subtypes of human parainfluenza virus. For example, one or more compounds of Formula (I), or a pharmaceutically⁷ acceptable salt thereof, can be used to treat HPIV-1 and/or HPIV-3.

[0188] The one or more compounds of Formula (I) or a pharmaceutically acceptable salt thereof, that can be used to treat, ameliorate and/or prevent a paramyxovirus

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PCT/US2014/051642 viral infection can be a compound of Formula (I), or pharmaceutically acceptable salt thereof, provided in any of the embodiments described in paragraphs [0078]-[0159], [0189] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes. and. in particular, humans. In some embodiments, the subject is human.

[0190] As used herein, the terms “prevent” and preventing, mean lowering the efficiency of viral replication and/or inhibiting viral replication to a greater degree in a subject who receives the compound compared to a subject who does not receive the compound. Examples of forms of prevention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as a paramyxovirus (e.g., RSV).

[0191] As used herein, the terms “treat.” treating.” treatment,” therapeutic.” and “therapy do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance, and may positively affect one or more symptoms or aspects of the disease while having effects on other aspects of the disease or on unrelated systems that may be considered undesireable.

[0192] The terms “therapeutically effective amount and “effective amount are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. For example, a therapeutically effective amount of compound can be the amount needed to prevent, treat, alleviate or ameliorate one or more symptoms or conditions of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated,

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PCT/US2014/051642 and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.

[0193] Various indicators for determining the effectiveness of a method for treating a viral infection, such as a paramyxovirus, are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a reduction in viral load, a reduction in viral replication, a reduction in viral RNA, a reduction in time to seroconversion (virus undetectable in patient serum), a reduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.

[0194] In some embodiments, an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, is an amount that is effective to reduce viral titers to essentially undetectable or very⁷ low levels, for example, to less than 1.7 logio plaque forming units equivalents (PFUe)/mL, or less than 0.3 logio plaque forming units equivalents (PFUe)/mL. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can reduce the viral load compared to the viral load before administration of the combination (for example, 60 hours after receiving the initial dosage of the combination). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can reduce the viral load to lower than 1.7 logio (PFUe)/mL, or lower than 0.3 logio (PFUe)/mL. In some embodiments, a combination of compounds described herein can achieve a reduction in viral titer in the serum of the subject in the range of about 1.5-log to about a 2.5-log reduction, about a 3-log to about a 4-log reduction, or a greater than about 5-log reduction compared to the viral load before administration of the combination. For example, the viral load is measure before administration of the combination, and several hours after receiving the initial dosage of the combination (for example, 60 hours after receiving the initial dosage of the combination).

|0195] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in at least a 1, 2. 3. 4. 5. 10, 15. 20, 25, 50. 75, 100-fold or more reduction in the replication of a paramyxovirus relative to pre-treatment levels in a subject, as determined several hours after receiving the initial dosage of the combination (for

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PCT/US2014/051642 example, 60 hours after receiving the initial dosage of the combination). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, described herein can result in a reduction of the replication of a paramyxovirus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can result in a reduction of a paramyxovirus replication in the range of 1 to 1.5 log. 1.5 log to 2 log. 2 log to 2.5 log. 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more reduction of a paramyxovirus replication compared to the reduction of a paramyxovirus reduction achieved by ribavirin (Virazole®), or may achieve the same reduction as that of ribavirin (Virazole®) therapy in a shorter period of time, for example, in one day. two days, three days, four days, or five days, as compared to the reduction achieved after 5 days of ribavirin (Virazole®) therapy.

[0196] After a period of time, infectious agents can develop resistance to one or more therapeutic agents. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a resistant virus may be reduced to a lesser degree compared to the amount in viral load reduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered to a subject infected with RSV that is resistant to one or more different anti-RSV agents (for example, ribavirin). In some embodiments, development of resistant RSV strains is delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, compared to the development of RSV strains resistant to other RSV drugs.

[0197] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can decrease the percentage of subjects that experience complications from a RSV viral infection compared to the percentage of subjects that experience complication being treated with ribavirin. For example, the percentage of subjects being treated with a compound of Formula (I), or a pharmaceutically acceptable salt thereof, that experience complications can be 10% . 25%, 40%. 50%, 60%, 70%. 80% and 90% less compared to subjects being treated with ribavirin.

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PCT/US2014/051642 [0198] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition that includes a compound described herein, can be used in combination with one or more additional agent(s). In some embodiments, a compound of Formula (1). or a pharmaceutically acceptable salt thereof, can be used in combination with one or more agents currently used in a conventional standard of care for treating RSV. For example, the additional agent can be ribavirin, palivizumab. and RSV-IGIV. For the treatment of RSV, additional anti-RSV agents include but are not limited to an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, an interferon and an other compound that inhibits the RSV virus, or a pharmaceutically acceptable salt of any of the foregoing. A non-limiting list of examples of additional agents is provided herein.

anti-RSV antibodies

RSV-IGIV (RespiGam®) palivizumab (Synagis®, a chimeric humanized IgG monoclonal antibody) motavizumab (MEDT-524. humanized monoclonal antibody)

fusion protein inhibitors

1- cyclopropyl-3-[[l-(4-hydroxybutyl)benzimidazol-2- yl]methyl]imidazo[4.5-c]pyridin-2-one (BMS-433771) 4.4-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]- (1,3,5)triazin-2-ylamino} -biphenyl-2,2-disulfonic-acid (RFI-641) 4,4'-Bis[4.6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)sulfonilimino]-1.3,5-triazine-2-ylamino]-biphenyl-2.2'-disulfonic acid, disodium salt (CL3 87626) 2- [[2-[[l-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-lHbenzimidazol-1 -yl]-6-methyl-3-pyridinol (JNJ-2408068) 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3(morpholin-4-yl)propyl]amino]benzimidazol-l-yl]methyl]-6methylpyridin-3-ol (TMC-353121) 5,5'-bis[l-(((5-amino-lH-tetrazolyl)imino)methyl)]2,2',4methylidynetrisphenol (VP-14637, MDT-637) N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl- [1,2.4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (Pl 3) 2-((2-(( 1 -(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1Hbenzo[d]imidazol-1 -yl)methyl)-6-methylpyridin-3-ol (RI 70591) 1.4-bis(3-methylpyridin-4-yl)-l,4-diazepane (Cl5) (R)-9b-(4-chlorophenyl)-1 -(4-fluorobenzoyl)-2,3-dihydro-1Himidazo[r,2':l,2]pyrrolo[3.4-c]pyridin-5(9bll)-one (BTA9981) [2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy4,7.8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2nonulopyranosid]onate (MBX-300)

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	BTA-C286 N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-l-yl)-6-methylpyrazolo[l,5a]pyrimidin-2-yl)piperidine-1 -carbonyl)-4- chlorophenyl)methanesulfonamide (GS-5806) an anti-RSV nanobody (e.g., ALX-0171 (a trivalent nanobody, Ablynx) a peptide fusion inhibitor (such as a peptide having the sequence DEFDAS1SQVNEK1NQSLAF1RKSDELL (T-67) a peptide having the sequence FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-l 18)
N-protein inhibitors	(S)-1 -(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro- 1Hbenzo\|cj[l,4]diazepin-3-yl)urca (RSV-604) STP-92 (siRNA delivered through nanoparticle based delivery systems, Sirnaomics) iKT-041 (Inhibikase)
RSV polymerase inhibitors	6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl] -N-cyclopropyl-5.6dihydiO-4H-thieno[3,2-d][l]benzazepine-2-carboxamide (YM-53403) N-cyclopropyl-5-(4-(2-(pyrrolidin-l-yl)benzamido)benzoyl)-5,6.7,10tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-Ncyclopropyl-5.6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2carboxamide. 4-amino-8-(3-{[2-(3,4dimethoxyphenyl)ethyl]amino]propyl)-6,6-dimethyl-2-(4-methyl-3nitrophenyl)-lH-imidazo[4,5-h]-isoquinoline-7.9(6EL8H)-dione (CAS Reg. No. 851658-10-1) AZ27
1MPDH inhibitors	ribavirin 5-ethynyl-1 -beta-D-ribofuranosylimidazole-4-carboxamide (EICAR) 4-hydroxy-3-beta-D-ribofuranosvlpyrazole-5-carboxamide (pyrazofurin) 1- ((2R,3R.4S,5R)-3.4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2yl)-1H-1.2,4-triazole-3-carboximidamide (Taribavirin. viramidine) l,3,4-thiadiazol-2-ylcyanamide (LY253963) tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5- yl)phenyl)ureido)benzvlcarbamate (VX-497) (4E)-6-(4-Hydroxy-6-methoxy-7-mcthyl-3-oxo-1.3-dihydro-2benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid) 2- morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxolH-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil)
Interferons	Type 1 interferon Type 2 interferon Type 3 interferon an alpha-interferon (IFN-a) Pegylated interferon-alpha-2a (PEGASYS®)

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	Pegylated interferon-alpha-2b (PEG-INTRON®) interferon alfacon-1 (INFERGEN®) beta-interferon (IFN-β) lambda-interferon (lFN-λ)
other compounds	a double stranded RNA oligonucleotide 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomidc), N-(2-chloro-4-methylphcnyl)-2-((l -(4methoxyphenyl)-lH-benzo[d]imidazol-2-yl)thio)propanamide (.TMN3003) an intratracheal formulation of recombinant human CC10 (CG-100) high titer, human immunoglobulin (RI-001, ADMA Biologies Inc.) a non-neutralizing mAb against the G protein (mAb 131-2G) AEN-RSV01 (an siRNA agent with the sense strand sequence (5' to 3') GGCUCUUAGCAAAGUCAAGdTdT (SEQ ID NO. 3) and the antisense strand sequence (5' to 3') CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 4) ALN-RSV02
	Medi-559 Medi-534 Medi-557

ALN-RSV01 and/or ALN-RSV02 can be found in U.S. Publication No. 2009/0238772. filed Dec. 15, 2008 (Alnylani Pharmaceuticals).

ALX-0171 described in U.S. Publication No. 2012/0128669, filed June 7, 2010.

T-67. SEQ ID NO: 1. U.S. Patent No. 6,623.741. filed Feb. 29. 2000.

T-l18, SEQ ID NO: 2. U.S. Patent No. 6,623.741. filed Feb. 29, 2000.

[0199] Other examples of compounds that can be used in combination with a compound of Formula (I), or a pharmaceutically acceptable salt, include those provided in WO 2013/186333. published December 19. 2013; WO 2013/186332, published December 19, 2013; WO 2013/186335. published December 19. 2013; WO 2013/186334, published December 19. 2013; WO 2012/080447. published June 21. 2012; WO 2012/080449, published June 21. 2012; WO 2012/080450, published June 21, 2012; WO 2012/080451, published June 21, 2012; WO 2012/080446, published June 21, 2012; WO 2010/103306, published September 16, 2010; WO 2012/068622, published May 31, 2012; WO 2005/042530, published May 12. 2005; WO 2006/136561. published December 28. 2006; WO 2005/058869. published June 30. 2005; U.S. 2013/0090328. published April 11. 2013; WO 2014/009302. published January 16. 2014; WO 2011/005842. published January 13. 2011; U.S. 2013/0273037. published October 17. 2013; U.S. 2013/0164280. published June 27. 2013; U.S. 2014/0072554. published March 13, 2014: WO 2014/031784, published

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February 27. 2014 and WO 2014/031784. published February 27, 2014, all of which are hereby incorporated by reference.

[0200] In combination therapy, the additional agents can be administered in amounts that have been shown to be effective for those additional agents. Such amounts are known in the art; alternatively, they can be derived from viral load or replication studies using the parameters for “effective amount” set forth above. Alternatively, the amount used can be less than the effective monotherapy amount for such additional agents. For example, the amount used could be between 90% and 5% of such amount, e.g.. 90%, 80%, 70%, 60%. 50%, 40%. 30%. 20%, 10%, or 5%, or intermediate values between those points.

10201] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

[0202] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prior to all additional agents. In other embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (1), or a pharmaceutically acceptable salt thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of at least one additional agent. In some embodiments, a compound of

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Formula (I), or a pharmaceutically acceptable salt thereof, can be administered subsequent to the administration of all additional agents.

[0203] A potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may be a reduction in the required amount(s) of one or more compounds of paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example. RSV). as compared to the amount required to achieve same therapeutic result when one or more compounds described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts thereof, are administered without a compound of Formula (I), or a pharmaceutically acceptable salt thereof. For example, the amount of a compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, can be less compared to the amount of the compound described in paragraphs [0198]-[0199] (including the table), including a pharmaceutically acceptable salt and prodrug thereof, needed to achieve the same viral load reduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (1). or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of resistant viral strains compared to the barrier when a compound is administered as monotherapy.

[0204] Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross resistance between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof); different routes for elimination of a

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PCT/US2014/051642 compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agcnt(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof): little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table) (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and one or more additional agent(s) described in paragraphs [0198]-[0199] (including the table), including pharmaceutically acceptable salts and prodrugs thereof).

[0205] As will be readily apparent to one skilled in the art. the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age. weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

[0206] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingredient, preferably between 1 mg and 700 mg. e.g. 5 to 200 mg. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed bv the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0207] In instances where human dosages for compounds have been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established

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PCT/US2014/051642 human dosage. Where no human dosage is established, as will be the case for newlydiscovered pharmaceutical compositions, a suitable human dosage can be inferred from ED.so or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0208] In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art. in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.

[0209] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However. HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0210] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

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PCT/US2014/051642 [0211] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.

Synthesis [0212] Compounds of Formula (I), and those described herein may be prepared in various ways. Some compounds of Formula (I) can be obtained commercially and/or prepared utilizing known synthetic procedures. General synthetic routes to the compounds of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

EXAMPI.ES [0213] Additional embodiments are disclosed in further detail in the following examples, w hich are not in any w ay intended to limit the scope of the claims.

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EXAMPLE 1

Preparation of Compound 1

[0214] To a mixture of 1-1 (3.65 g, 20 mmol) in NMP:THF (2 niL/20 mL), Fe(acac);, (622 mg, 2 mmol) was added. The solution was cooled to 0°C and i-PrMgCl (20 mL, 2N) was added slowly at 0°C. The solution was stirred for 2 h at 0°C. The solution was extracted with EA, and washed with brine. The organic phase was concentrated to give crude 1-2 as a colorless solid (2.4 g, 63.5%). +ESI-MS: m/z 190.1 [M+H]⁺.

[0215] To a mixture of 1-2 (1 g, 5.29 mmol) and 1-3 (1.03 g, 5.29 mmol) in DMF (30 mL) were added Pd(dppf)C12 (420 mg, 0.529 mmol) and a freshly prepared KF solution (2.57 g in 10 mL of water). The system was degassed and then charged with nitrogen 3 times. The mixture was stirred under nitrogen at 70°C using an oil bath for 8 h. The reaction solution was cooled to r.t.. diluted with EA and separated from the water layer. The EA solution was washed with brine, dried over Na^SCfi and concentrated. The residue was

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PCT/US2014/051642 purified on a silica gel column to give 1-4 as a colorless solid (0.5 g, 31%). +ESI-MS: m/z 306.0 [M+II]'/ [0216] To a mixture of 1-4 (900 mg, 2.95 mmol). 1-5 (1.07 g, 2.95 mmol) and I<F (0.684 g. 11.8 mmol) in DMF (10 mL) was added Pd(dppf)C12 (228 mg, 0.295 mmol). The system was degassed and then charged with nitrogen 3 times. The mixture was stirred under nitrogen at 70°C using an oil bath for 8 h. The reaction solution was cooled to r.t., diluted with EA and H2O. The organic phase was washed with brine, dried over Na2SO4 and concentrated to give crude 1-6 (1 g). +EST-MS: m/z 342.1 [M+H]⁺.

[0217] A mixture of 1-6 (1 g. 2.9 mmol) and NBS (516 mg, 2.9 mmol) in a mixture of THF (10 mL) and FLO (1 mL) was stirred at r.t. for 30 mins. The solution was diluted with water and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with a sat. Na2S20s solution, followed by brine. The solution was dried over Na2SO4 and evaporated to give crude 1-7 (1 g). +ESI-MS: m/z 392.0 [M+H]⁺.

[0218] To a solution of 1-7 (1 g, 2.55 mmol) in a mixture of THF (5 mL) and MeOH (0.5 mL) was added NaBlfi (193 mg, S.lmmol) at 0°C. The mixture was stirred at 0°C for 30 mins with TLC monitoring. The reaction was quenched by the addition of H2O and extracted with EA. The combined organic layers were washed with brine, dried over NibSO i and concentrated. The residue was purified on a silica gel column to give 1-8 (200 mg, 20%). +ESI-MS: m/z 394.0 [M+H]⁺.

[0219] A mixture of 1-8 (200 mg. 0.50 mmol) and sat. NHiOH/EtOH (1 mL/5 mL) in a sealed tube was heated to 70°C for 6 h. The solution was removed under reduced pressure to give crude 1-9 (160 mg, 90.0%). which was used for next step directly without purification. +ESI-MS: m/z 331.1 [M+H]⁺.

[0220] To a solution of 1-9 (65 mg, 0.363 mmol). HATU (172 mg, 0.45 mmol) and DIPEA (117 mg. 0.909 mmol) in anhydrous DMF (1 mL) was added 1-10 (100 mg 0.303 mmol) at 25‘’C. The solution was stirred for 10 h at r.t. The solution was diluted with 1.0 N aqueous NaHCCL solution (2 x 40 mL) and extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 1 (100 mg. 67.1%). +ESI-MS: m/z 495.1 [M+H]⁺.

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EXAMPLE 2

[0221] A solution of 2,4.6-trichloropyridine (6.5 g, 36 mmol) in anhydrous methanol (20 mL) was added MeONa (2.9 g, 54 mmol) at 0°C. The reacton mixture was stirred at r.t. for 12 h. The reaction was quenched with dry ice. and the mixture was filtered. The solution was concentrated under reduced pressure, and the residue was dissolved in EA. The mixture was washed with water, and the organic layers were dried over NaSCfr The solvent was concentrated to give 1-12 (4.2 g, 67%).

[0222] Compound 100 was prepared using 1-12 and 4-(cyclopropylmethoxy)-3methoxybenzoic acid, and by following a synthetic route, which closely follows that described for the preparation of 1. 100: +ESI-MS: m/z 483. 1 [M+H]+.

EXAMPLE 3

Preparation of Compound 101

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[0223] To a solution of 2-1 (3 g, 14 mmol) and the boronic acid (2.5 g, 14 mmol) in dioxane/H?O (30 mL/5 mL) was added Pd(dppf)Cl? (1.02 g, 1.4 mmol) and CS2CO3 (6.8 g, 21 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 2 h. The solution was cooled to r.t., diluted with EA and separated from the water layer. The EA solution was washed by brine, dried over Na^St ) | and concentrated. The residue was purified on a silica gel column to give 2-2 (2 g, 47.9%).

[0224] To a solution of 2-2 (2 g, 6.7 mmol) in MeOlI/DCM (20 mL/20 mL) was added NaBTfi (510 mg. 13.4 mmol) slowly at 0°C. The solution was stirred for 10 mins and heated to 50°C and stirred for 2 h. The solution was quenched with Η₂Ο and extracted with EA. The solution was concentrated to give crude 2-3 (1.81 g, 100 %).

[0225] To a solution of 2-3 (1.81 g. 6.7 mmol) in DMF was added imidazole (1.36 g, 1.34 mmol) at r.t. TBSC1 (201 mg, 1.34 mmol) was added. The solution was stirred for 18 h. The solution was washed with waler and extracted with EA. The organic phase was concentrated to give 2-4 (1.8 g, 70.0%). ESI-LCMS: m/z 385.9 [M+H]⁺.

[0226] Compound 2-10 was prepared using 2-4 and 4-(cyclopropylmethoxy)-3methoxybenzoic acid, and by following a synthetic route, which closely follows that described for the preparation of 1. 'H-NMR (400 MHz, CDClj), δ = 8.00 (d, ./=5.51 Hz. 1 H) 7.87 (br. s„ 1 H) 7.78 (s, 1 H) 7.81 (s, 1 H) 7.34 (s, 1 H) 7.26 (d, ./=8.38 Hz, 1 H) 7.14 (t, ./=8.71 Hz, 1 H) 6.92 (br. 1 H) 6.74 (d, ./=8.38 Hz. 1 H) 5.13 (d, ./=4.41 Hz, 2 H) 4.72 (s, 2

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Η) 3.71-3.85 (m, 5 Η) 1.09 (hr, 1 Η), 0.83 (s, 10 Η) 0.46-0.56 (m, 2 Η), 0.19-0.30 (m, 2 Η), 0.00 (s, 7 Η).

[0227] To a solution of 2-10 (100 mg. 0.163 mmol) in dioxane (2 mL) was added concentrated HC1 (2 mL) at r.t. and the mixture was stirred for 30 mins. The solution was quenched by aqueous NaHCO? solution and extracted by EA. The combined organic layers were washed by brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC(FA) to give 2-11 (30 mg, 37.0%) as a white solid. +ESI-MS: m/z 498.9 [M+H]⁺.

[0228] The solution of 2-11 (100 mg, 0.20 mmol) in THF (2 mL) was added MeMgBr (1 mL, 3 mmol) at r.t. and the mixture was stirred for 2 h. The solution was quenched with H₂O and extracted with EA. The combined organic layers were washed by brine, dried over Na2SO4 and concentrated. The residue was purified by prep-TLC (PE:EA=1:1) to give 101 (20 mg. 19.4%) as a white solid. +ES1-MS: m/z 514.9 [M+H]⁺.

EXAMPLE 4

Preparation of Compound 102 ^XO [0229] To a solution of 3-1 (3.4 g, 40 mmol) in THF (50 mL) at r.t. was added NBS (14 g, 80 mmol). The mixture was stirred for 1 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=2:1) provided 3-2 as white solid (9.6 g, 99%). +EST-MS: m/z 239.0 [M+H]+ [0230] To a solution of 3-2 (9.6 g. 40 mmol) and K2CO3 (5.4 g. 40 mmol) in DMF (50 111L) at 40°C was added CH3I (6 g, 40 mmol). The mixture was stirred for 2 h at r.t. The solution was poured into water and extracted with EtOAc. The organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA=20:l) to provide 3-3 (3 g. 30%). +ES1-MS: 111/z 253.0 [M+H]+.

[0231] Compound 102 was obtained by closely following the procedure for obtaining 1 using 3-3 and 3,4-dimethoxybenzoic acid. Compound 102 was obtained as a white solid. +ES1-MS: m/z 470.1 [M+H]⁺.

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EXAMPLE 5

Preparation of Compound 103

4-1 [0232] To a stirring mixture of 2,6-dichloropyridine (270 mg, 1.82 mmol) and 7fluoro-lH-benzo[d]imidazole (248 mg, 1.82 mmol) in DMF (3 mL) was added CS2CO3 (709 mg, 2. 2 mmol). The mixture was reacted at 120°C for 2 h and then cooled to r.t. The mixture was diluted with EtOAc and washed with a sat. NaCl solution. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Chromatography of the residue afforded 4-1 (300 mg) as a white solid. LCMS: m/z 248.1 [M+H]⁺.

[0233] Compound 103 was obtained as a yellow oil (100 mg) bv closely following the procedure for obtaining 1 using 4-1 and 3,4-dimethoxybenzoic acid. LCMS: m/z 437.25 [M+H]⁺.

EXAMPLE 6

Preparation of Compound 104

F F

5-8	5-9
F			F
	s	NaH/MOMCI	s
[II	^XDH		^XDMOM
5-10	Br		5-4 Br

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Cl

5-1

5-2

Cl

Sn(CH₃)₃

OPMB

Pd(PPh₃)₄, toluene

[0234] To a solution of 5-1 (10 g, 44.0 mmol) in DMF (150 mL) was added NaH (7.0 g, 0.177 mol), and the mixture was stirred at 0°C for 30 mins. The solution was treated with PMBC1 (11.67 g. 0.0748 mol), and stirred at r.t. overnight. After complete conversion, the reaction was quenched with MeOH and H₂O, and extracted with EA. The organic phase was concentrated to give 5-2 (11 g. 87.2%). +ES1-MS: m/z 375.9 [M+H]⁺.

|0235] To a solution of 5-2 (36 g. 96 mmol) in toluene (400 mL) was added (CH₃)₆Sn₂ (47.0 g, 144.0 mmol). The mixture was bubbled with nitrogen gas and stirred at 100°C for 3 h. The mixture was concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-3 (22 g). +ES1-MS: m/z 414.0 [M+H]⁺.

[0236] To a solution of 5-8 (30 g, 134 mmol) in anhydrous THF (500 mL) was added L1AIH4 (7.6 g, 200 mmol) in portions at 0°C, and the mixture was stirred at r.t. for 2 h (monitored by TLC). The reaction was quenched with a sat. NH4CI solution, and extracted with EA to give the crude product, which was purified by column chromatography to give 59 (22 g). +ESI-MS: m/z 183.0 [M+H]⁺.

[0237] To a solution of 5-9 (22 g, 121 mmol ) in THF (400 mL) was added NBS (25.7 g. 145 mmol), and the mixture was stirred at r.t. overnight (monitored by TLC). The reaction was quenched with a sat. Na₂S₂O₃ solution, and extracted with EA to give the crude product . which was purified by column chromatography to give 5-10 (23 g). +ESI-MS: m/z 460.9 [M+H]⁺.

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PCT/US2014/051642 [0238] To a solution of 5-10 (22 g, 84.6 mmol) in anhydrous THF (200 mL) was added Nal I (8.12 g, 33.85 mmol) in portions at 0°C, and the mixture was stirred at 0°C for 30 mins. MOMCI (27.08 g, 338.5 mmol) was added, and the mixture was stirred at r.t. for 4 h. The reaction was quenched with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-4 (21 g). +ESI-MS: m/z 304.9 [M+H]⁺.

[0239] To a solution of 5-3 (6.36 g, 15.4 mmol) in DMF (50 mL) were added 5-4 (4.7 g. 15.4 mmol). KF (3.7 g, 61.6 mmol) and Pd^PhafiCF (324 mg, 0.46 mmol). The mixture was bubbled with nitrogen gas and stirred at 100°C overnight. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-5 (3.8 g). +ESI-MS: m/z 474.1 [M+H]⁺.

[0240] To a solution of 5-5 (4.5 g, 9.51 mmol) in THF (30 mL) was added 10% HC1 (30 mL), and stirred 110°C overnight. The mixture was cooled to r.t.. and the pH was adjusted to 7.0 by adding a sat. Nal ICCb solution. The mixture was extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give 5-6 (2.0 g), which was used in the next step without purification. +ES1-MS: m/z 310.0 [M+H]⁺.

[0241] To a solution of 5-6 (1.3 g, 4.2 mmol) in THF (100 mL) was added PPhj (1.32 g. 5.05 mmol), and the mixture was stirred at r.t. for 10 mins. DIAD (1.01 g. 5.05 mmol) was added in portions, and the mixture stirred at refluxed for 4 h. The mixture was concentrated in vacuum to give the crude product, which was purified by column chromatography to give 5-7 (0.7 g). +ESI-MS: m/z 292.0 [M+H]⁺.

[0242] Compound 104 was obtained as a white solid (50 mg) by closely following the procedure for obtaining 1 by using 5-7 and 3,4-dimethoxybenzoic acid. +ES1-MS: m/z 481.1 [M+H]⁺.

EXAMPLE 7

Preparation of Compound 105

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PCT/US2014/051642 [0243] To a solution of 6-1 (196 mg, 1.0 mmol), l,4-dibromobutane-2,3-dione (241 mg, 1.0 mmol) in DCM (3 mL) was added AgOTf (255mg. 1.0 mmol). Lhe reaction was carried out at 80°C under microwave irradiation for 15 mins. Lhe mixture was concentrated at low pressure. The residue was purified by silica gel column (PE/EA) to 6-2 (270 mg. 80%). +ESI-MS: m/z 339. 9 [M+H]⁺.

[0244] Compound 105 was obtained (100 mg, 48 %) by closely following the procedure for obtaining 1 using 6-2 and 3,4-dimethoxybenzoic acid. +ESI-MS: m/z 442. 9 [M+H]⁺.

[0245]

Compound 106 was prepared using 2,6-dibromopyridine.

2-(7fluoiObenzo[b]thiophen-3-yl)-4.4,5.5-tetramethyl-L3,2-dioxaboiOlane and

3,4dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-MS: m/z 452.9 [M+H]⁺.

[0246] Compound 107 was prepared using 3,4-dimethoxybenzoic acid and 3 bromo-5-(7-fluorobenzo[b]thiophen-3-yl)-l-piOpyl-lH-l,2,4-triazole, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ES1-MS: m/z 485.0 [M+H]⁺.

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PCT/US2014/051642 [0247] Compound 108 was prepared using 2,4-dibromothiazole, 2-(7fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-l ,3.2-dioxaborolane and 3.4dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ESI-LCMS: m/z 459.0 [M+H]+.

[0248] Compound 109 was prepared using 2,4-dichloro-5-methoxypyrimidine. (3chloro-4-fluorophenyl) boronic acid and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for preparation of 1.

[0249] Compound 110 was prepared using 2-hydroxy-4,5-dimethoxybenzoic acid and 2-amino-l-(6-(7-fluorobenzo[b]thiophen-3-yl)-4-methoxypyridin-2-yl) ethanol, and by following a synthetic route, which closely follows that described for preparation of 1. Compound 110 was obtained as a white solid. +ESI-MS:m/z 498.9[M+I I]⁺.

[0250] Compound 111 was obtained by closely following the procedure for obtaining 1 by using 2,4-dibromothiazole, 2-(7-fluorobenzo[b]thiophen-3-yl)-4,4.5,5 tetramethyl-l,3,2-dioxaborolane and 3,4-dimethoxybetrzoic acid. Compound 111 was obtained as a white solid. +ESI-LCMS: m/z 466.9 [M+H]⁺.

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[0251] Compound 112 was prepared using 4-chloro-2-iodo-6-methoxypyrimidine, 2-(7-fluorobenzo[b]thioplien-3-yl)-4,4.5,5-tetramethyl-1.3,2-dioxaborolane and 3.4dimethoxybenzoic acid, and by following a synthetic route, which closely follows that described for preparation of 1. +ESI-MS: m/z 484.1 [M+H]⁺.

EXAMPLE 8

Preparation of Compound 113

Sn(nBu)₃ iPrMgCI

NBS

KF,Pd(dppf)CI₂,

DMF, 80°C,15 h

Cs₂CO3,Pd(dppf)Cl2,

DMF, 80°C,15 h

1) TMSOTf,

DIPEA,

DCM, 0°C

2) NBS, THF

[0252] To a solution of 7-1 (7.5 g, 27.17 mmol) in THF (100 mL) was added slowly i-PrMgCl (2? mL, 2M in THF) at r.t., and the mixture stirred lor 10 mins. The

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PCT/US2014/051642 solution was quenched with MeOH and diluted with DCM (20 mL). The solution was washed by brine, dried over NajSCfi and concentrated to give crude 7-2 (5 g, 94.3 %).

[0253] To a solution of 7-2 (1 g, 5.1 mmol), the tin reagent (3.71 g, 10.2 mmol) and KF (1.18 g. 20.4 mmol) in DMF (10 mL) was added Pd(dppf)Cb (372 mg, 0.51 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 15 h. The solution was cooled to r.t. The mixture was diluted with EA. The EA solution was washed by brine, dried over Na^SCU and concentrated to give crude 7-3 (360 mg. 44.2%) [0254] To a solution of 7-3 (360 mg, 2.25 mmol) in DCM (5 mL) was added NBS (480 mg. 2.7 mmol). The mixture was stirred at r.t. for 30 mins with TLC monitoring. The solution was quenched by aqueous Na₂S₂O₃ solution and extracted by EA. The combined organic layers were dried over Na₂S( ) | and concentrated. The residue was purified by prepHPLC(FA) to give 7-4 (250 mg, 46.2%) .

[0255] To a solution of 7-4 (480 mg, 2 mmol) and the dioxaborolane reagent (558 mg, 2 mmol) in dioxane/I LO (10 mL/2 mL) were added Pd(dppf)CL (146 mg, 0.2 mmol) and CS2CO3 (975 mg. 3 mmol). The system was degassed and then charged with nitrogen for 3 times. The mixture was stirred under nitrogen at 80°C in an oil bath for 15 h. The solution was cooled to r.t.. diluted with EA and separated from the water layer. The EA solution was washed by brine, dried over Na₂SC>4 and concentrated. The residue was purified on a silica gel column to give 7-5 (400 mg, 64.5%).

[0256] To a solution of 7-5 (550 mg, 1.77 mmol) in DCM (5 111L) was added DIPEA (685 mg. 5.31 mmol) and TMSOTf (589 mg, 2.65 mmol) at 0°C. The solution was stirred for 2 h at r.t. The solution was concentrated and the residue was dissolved in THF (10 mL) and FLO (1 mL). NBS (471 mg, 2.65 mmol) was added at r.t., and stirred for 1.5 h. The solution was evaporated at low pressure. The residue was purified by chromatography (PE:EA=3:1) to give 7-6 (600 mg. 86.9%).

[0257] Compound 113 was prepared from 7-6 and 3,4-dimethoxybenzoic acid by following a synthetic route, which closely follows that described for the preparation of 1. Compound 113 was obtained as white solids. +ESI-MS: m/z 492.0 [M+H]⁺.

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[0258] To a solution of 8-1 (90 mg, 0.19 mmol) in THF (5 mF) was added CFEMgBr (3 M. 0.64 M) at 0°C. and stirred at r.t. overnight. The reaction was quenched with NHqCl solution and extracted with EA. The organic layer was dried over sodium sulfate, then concentrated in vacuum to give the crude product . which was purified by prepHPLC to give 114 (18 mg) as a white solid. +ES1-MS: m/z 498.1 [M+H]⁺.

[0259] Compound 115 (57 mg, 60%) was obtained by closely following the procedure for obtaining 114 by using 9-1 (120 mg, 0.2 mmol). Compound 115 was obtained as a white solid. +ESl-MS:m/z 494.9 [M+H]⁺.

[0260] Compound 116 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fhioro-3-(4,4.5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-l-((2(trimethylsilyl)ethoxy)niethyl)-lH-indole and 4-ethoxy-3-methoxybenzoic acid. Compound 116 was obtained as a white solid. +ESI-MS; 111/z 494.2 [M+H]⁺.

[0261] Individual enantiomers of 116 (116a and 116b) were obtained by SFC separation of a racemic mixture of 116. +ESI-MS: m/z 494.2 [M+H]⁺.

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PCT/US2014/051642 [0262] Compound 117 was obtained by closely following the procedures for obtaining 100 and 114 using 7-fluoro-3-(4,4.5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-l-((2(trimcthylsilyl)ethoxy)methyl)-lH-indolc and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid.

Compound 117 was obtained as a white solid. +ESI-MS: m/z 510.2 [M+H]⁺.

[0263] Individual enantiomers of 117 (117a and 117b) were obtained by SFC separation of a racemic mixture of 117. +ESI-MS: m/z 510.1 [M+H]⁺.

[0264] Compound 118 was prepared using l-amino-2-(6-(3-bromo-4fluorophenyl)-5-methoxypyridin-2-yl)propan-2-ol and 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 4-(2-fluoroethoxy)-3-methoxybenzoic acid, and by following a synthetic route, which closely follows that described for preparation of 100 and 114. +ESI-MS: m/z 551.9 [M+H]⁺.

[0265] Individual enantiomers of 118 (118a and 118b) were obtained by SFC separation of a racemic mixture of 118. +ESI-MS: m/z 551.9 [M+H]⁺.

[0266] To a stirring mixture of N-(2-(6-(3-chloro-4-fluorophenyl)-5methoxypyridin-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3-methoxybenzamide (50 mg. 0.1 mmol) in THF at r.t. under argon was added a solution of MeMgCI in THF (0.5 mF, 1.0 mmol). The mixture was reacted at r.t. for 2 h. The mixture was diluted with EtOAc and slowly quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 10 mins and then the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na₂SO4). filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel column and further purified via prep-HPEC to afford 119 as a white solid. FCMS: 111/z 507.1 [M+H]⁺.

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[0267] Compound 120 was prepared using N-(2-(6-(3-chloro-4-fluorophenyl)-5iiiethoxypyridiii-2-yl)-2-oxoethyl)-4-(2-hydroxyethoxy)-3-methoxybenzamide with MeMgBr in THF. and by closely following a synthetic route, which closely follows that described for preparation of 119. LCMS: m/z 505.15 [M+H]⁺.

[0268] Individual enantiomers of 120(120» and 120b) were obtained by SFC separation of a racemic mixture of 120. +ESI-MS: :m/z 505.1 [M+H]⁺.

[0269] Compound 121 was prepared using N-(2-(6-(3-chloro-4fluorophenyl)pyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(2-(methylamino)-2oxoethoxy)benzamide with MeMgBr in THF. and by following a synthetic route, which closely follows that described for preparation of 119. LCMS: m/z 502.05 [M+H]⁺.

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PCT/US2014/051642 [0270] Compounds 122, 123, 124,125,126 and 127 were prepared using N-(2-(6(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-2-oxoethyl)-4-(2-fluoroethoxy)-3methoxybenzamide with different Grignard reagents in THF, and by following a synthetic route, which closely follows that described for preparation of 119. 122: LCMS: m/z 521.15 [M+H]⁺. 123: LCMS: m/z 533.15 [M+H]⁺. 124: LCMS: m/z 531.10 [M+H]⁺. 125: LCMS: m/z 535.15 [M+H]⁺. 126: LCMS: m/z 519.15 [M+H]⁺. 127: LCMS: m/z 517.05 [M+H]⁺.

[0271] Individual enantiomers of 122 (122a and 122b) were obtained by SFC separation of a racemic mixture of 122.

Cl [0272] Compound 128 was prepared using N-(2-(6-(3-chloro-4-fluoropheny 1)-5methoxypyridin-2-yl)-2-oxoethyl)-3-methoxy-4-(1 H-pyrazol-1 -yl)benzamide with MeMgBr in THF. and by following a synthetic route, which closely follows that described for preparation of 119. LCMS: m/z 511.10 [M+H]⁺.

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EXAMPLE 9

Preparation of Compound 129

[0273] A 50 mL flask with a magnetic stirring bar was charged with 10-1 (223 mg. 1.0 mmol). Weinreb amide (10-2, 282 mg. 1.0 mmol), and THF (10 mL) under N? atmosphere. The solution was treated with i-PrMgCl (1.3 M. 2.0 eq.) dropwise at r.t. The mixture was stirred for 1 h at r.t. Water (50 mL) and EA (50 mL) were added. The organic layer was separated and the aqueous phase extracted with EA. The combined organic layers were dried with MgSC), and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel (PE) to provide 10-3 as a solid (332 mg, 90%). +ESI-MS: m/z 367.0. 369.0 [M+H]⁺.

[0274] To a stirred solution of 10-3 (368 mg, 1.0 mmol) in MeOH/THF (5 mL/5 mL) was added NaBFLi (380 mg, 10 mmol) in portions until the starting materials was consumed. The volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EtOAc=2:l) to give 10-4 as a colorless oil (370 mg, 100%). +ESI-MS: m/z 369.0, 371.0 [M+H]⁺.

[0275] A 50 mL flask with a magnetic stirring bar was charged with 10-4 (165 mg. 0.5 mmol). 2-(7-fluorobenzo[b]thiophen-3-yl)-dioxaborolane (278 mg. 1.0 mmol).

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Pd(dppf)Cl₂ (8 mg, 1 mol%), KF (180 mg, 3.0 mmol), and dioxane/I I₂O(20 mL/5 mL) under

N₂ atmosphere. The mixture was stirred for 10 h at 100°C. Water (50 mL) and EA (50 mL) were added. The organic layer was separated and the aqueous phase extracted with EA. The combined organic phases were dried with MgSCfi and the volatiles were removed under reduced pressure. The residue was purified by column chromatography on silica gel to provide 129 as a white solid (176 mg. 80%). +ESI-MS: m/z 463.9 [M +Na]⁺.

[0276] Compound 130 was obtained following the procedure for obtaining 129 by using 10-2, 1.3-dibromoimidazo[l,5-a]pyridine and 2-(7-fluorobenzo[b]thiophen-3-yl)

4,4.5,5-tetramethyl-1.3,2-dioxaborolane as the starting materials, and then the oxidizing reagent DMP. Compound 130 was obtained as a white solid. +ES1-MS: m/z 489.8 [M+H]⁺.

[0277] Compound 131 (176 mg. 80%) was obtained following the procedure for obtaining 129 by using 10-2. 4-chloro-2-iodo-6-methoxypyrimidine and 2-(7fluorobenzo[b]thiophen-3-yl)-4,4,5.5-tetramethyl-l.3,2-dioxaborolane. +ESI-MS: m/z 483.9 [M+H]⁺.

EXAMPLE W

Preparation of Compound 132

[0278] Compound 11-1 was prepared using 10-2, 2,4,5-tribromo-1-((2(trimethylsilyl)cthoxy)mcthyl)-1 H-imidazolc and 3,4-dimcthoxy-N-(2-92WO 2015/026792

PCT/US2014/051642 (methoxy(methyl)amino)-2-oxoethyl)benzarnide, and by following a synthetic route, which closely follows that described for preparation of 129.

[0279] Compound 11-1 (402 mg, 0.62 mmol) was dissolved in TFA/DCM (1/1, 6 mL). and stirred at r.t. for 3 h. The solvent was removed and the residue was purified by column (DCM /MeOH= 50:1 to 20:1) on silica gel to give 132 (149 mg, 72.4%). +ESTMS:m/z 442.1[M+H]⁺.

[0280] Compound 133 was prepared using 2.4,5-tribromo-l-methyl-lH-imidazole and 3.4-dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide. and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS:m/z 455.9[M+H]⁺.

134 [0281] Compound 134 was prepared using 2,4-dibromothiazole and 3,4dimethoxy-N-(2-(methoxy(methyl)amino)-2-oxoethyl)benzamide, and by following a synthetic route, which closely follows that described for preparation of 129. +ESI-MS: m/z 459.0 [M+H]⁺.

O [0282] +ESI-MS: m/z 502.9 [M+H]⁺.

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EXAMPLE 11

Preparation of Compounds 136 and 137

136 & 137 [0283] A mixture of 12-1 (3.26 g, 9.80 mmol). (lR.2R)-2-aminocyclopentan-l-ol hydrochloride (1.04 g, 7.55 mmol), EDC (2.17 g, 11.3 mmol), HOBT (1.53 g, 11.3 mmol) and TEA (2.60 mL, 18.9 mmol) in DCM (50 mL) was stirred at r.t. for 18 h. The mixture was washed twice with IM aq. HC1 solution, dried (NajSCfi), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc. 100:0 to 0:100) afforded 12-2 as a white solid (2.98 g. 95%). UPTC/MS(ES⁺): m/z 416.29 [M+H]⁺.

[0284] Dess-Martin periodinane (4.55 g. 10.7 mmol) was added to a solution of 12-2 (2.98 g, 7.16 mmol) in DCM (50 mL). The mixture was stirred at r.t. for 1.5 h. A 1:1 mixture of 10% aq. Na2S2O3 solution and sat. aq. NaHCOs solution was added, and the mixture was stirred for 40 mins. The layers were separated and the organic portion was dried (Na₂SO4), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 100:0 to 0:100) afforded 12-3 as a white solid (2.86 g. 96%). UPLC/MS(ES⁺): m/z 413.18 [M+H]⁺.

[0285] n-Butyllithium (1.6M solution in hexane. 1.50 mL, 2.42 mmol) was added dropwise to a stirred solution of 12-4 (760 mg, 2.42 mmol) in toluene (15 mL), which had

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PCT/US2014/051642 been pre-cooled to -78°C. After 20 mins, a solution of 12-3 (500 mg, 1.21 mmol) in THF (10 mL) was added. The mixture was stirred at -78°C for 30 mins. The mixture was allowed to warm to r.t. and then quenched with MeOH. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The layers were separated and the organic portion was dried with Na2SO4. filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromathography (wateriCHsCN 100:0 to 95:5) to afford 12-5 as a 2:1 diastereomeric mixture (470 mg. 65%). UPLC/MS(ES⁺): m/z 601.22 [M+H]⁺.

[0286] A mixture of (3-chloro-4-fluorophenyl)boronic acid (50.5 mg. 0.290 mmol), 12-5 (70 mg, 0.116 mmol), Pd(dppf)C12 (4.3 mg, 0.006 mmol) and aq. Na2CO3 (2M solution, 174 uL, 0.348 mmol) in DCE (2 mL) was degassed and heated to 85°C. After 1 h, water was added and the aqueous phase was extracted with DCM. The organic phase was dried with Na^SCfi, filtered and concentrated under reduced pressure. The residue was dissolved in a 10:1 DCM-TFA solution (3 mL) and the mixture was stirred at r.t. for 30 mins. A IM aq. NaOH solution was added and the mixture was stirred for further 30 mins. The phases were separated and the organic portion was dried with Na^SCfi, filtered and concentrated under reduced pressure. Chromatography of the residue (DCM-MeOH, 98:2) afforded compounds 136 and 137. 136: UPLC/MS(ES⁺): m/z 531.26 [M+II]⁺. 137:

UPLC/MS(ES⁺): m/z 531.26 [M+H]⁺.

EXAMPLE 12

Preparation of Compound 138

13-1

[0287] Compound 13-1 was obtained following the procedure for obtaining 1 by using 2,4,6-trichloropyridine, 2-(7-fluorobenzo[b]thiophen-3-yl)-4.4,5.5-tetramethyl-l,3.2dioxaborolane and 3.4-dimethoxybenzoic acid.

[0288] To a solution of 13-1 (972 mg, 2 mmol) in DME (15 mL) was added 13-2 (616 mg, 4 mmol), Pd(dppf)C17(146 mg, 0.2 mmol) and Cs2CO₃(1.3 g, 4 mmol). The

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PCT/US2014/051642 mixture was stirred for 16 h at 120^l’C under N2. The reaction solution was filtered and to give a clear solution. The solution was extracted with EtOAc (80 mL) and washed with brine (3 x 20 mL). Compound 138 was purification by silica column chromatography using EA:PE = 1:1 as the elute (900 mg, 94%). ESI-MS: m/z 478.9 [M+H]⁺.

EXAMPLE 13

Preparation of Compound 139

[0289] To a solution of 14-1 (495 mg. 1.0 mmol) in MeOH (10 mL) was added aqueous NaOH (10 mL, IM). The mixture was stirred for 4 h at 60°C. The solution was cooled to r.t., acidified to pH 3 using IN HCI solution and extracted with EtOAc. The organic phase was dried with anhydrous \a2SO1 and concentrated under reduced pressure to provide 139 (490 mg, 99 %). +ES1-MS: m/z 497.1 [M+H]⁺.

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EXAMPLE 14

Preparation of Compounds 140 and 141

[0290] Compound 15-2 was prepared starting from 2-chloro-6-(hydroxymethyl)4-iodopyridin-3-ol (15-1) according to procedures provided in PCT Publication No. WO 2004/039366, published May 13, 2004, which is hereby incorporated by reference for the limited purpose of its disclosure of the preparation of 15-2.

[0291] Dess-Martin periodinane (2.00 g, 4.21 mmol) was added to a stirred solution of 15-2 (835 mg) in dry DCM (5 mL). The mixture was stirred at r.t. for 40 mins, and quenched with a 1:1 mixture of 2M aq. Na2S20a solution-sat. aq. NaHCCfi sol (10 mL). After 30 mins., the layers were separated. The organic portion was washed with brine, dried (Na₂SC>4), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 100:0 to 60:40) afforded 15-3 as a white solid (250 mg). *H NMR (400 MHz, CDClj) δ ppm 1.44 (s. 6 H). 4.53 (s, 2 H). 7.79 (s. 1 H), 9.92 (s. 1 H).

WO 2015/026792

PCT/US2014/051642 [0292] Nitromethane (191 uL, 3.54 mmol) and K7CO3 (32.5 mg, 0.236 mmol) were added to a solution of 15-3 (250 mg, 1.18 mmol) in dry THF (5 mL). The mixture was stirred at r.t. for 30 h and EtOAc was added. The organic portion was washed with water and brine, dried (Na?SO4). filtered and concentrated under reduced pressure to afford crude 15-4 (343 mg), which was used in the next step. 'H NMR (400 MHz, CDCI3) δ ppm 1.36 -1.49 (m, 6 H). 4.45 (s, 2 H). 4.68 (dd, 7=13.6, 8.5 Hz. 1 H). 4.85 (dd. 7=13.4. 3.4 Hz, 1 H). 5.43 (dd. 7=8.5. 3.3 Hz. 1 H). 7.26 (s, 1 H).

[0293] NaBHj (21.0 mg. 0.550 mmol) was added to a solution of NiCl2-6H?O (43.0 mg. 0.183 mmol) in MeOH (3 mL). After 30 mins, 15-4 (100 mg. 0.367 mmol) dissolved in MeOH (2 mL) was added, followed by additional solid NaBHj (28.0 mg. 0.730 mmol). The reaction was monitored by UPLC. When complete, the mixture was filtered through a pad of celite and the organic portion w as concentrated under reduced pressure. The residue was eluted through a SCX-cartridge using MeOH and 2M NH₃-MeOH solution to afford 15-5. UPLC/MS(ES⁺): m/z 243.10 [M+H]⁺.

[0294] A mixture of 15-5. 3-methoxy-4-{2-[(4methoxyphenyl)methoxy]ethoxy}benzoic acid (146 mg. 0.440 mmol), EDC (106 mg, 0.550 mmol). HOBT (74 mg, 0.550 mmol) and TEA (101 uL, 0.730 mmol) in DCM (4 111L) was stirred at r.t. for 18 h. The mixture was washed twice with IM aq. HC1 solution. The organic portion was dried with NaoSCq, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 0:100) afforded 15-6 as a pale yellow wax (90 mg, 44% over two steps). UPLC/MS(ES¹): m/z 557.30 [M+H]^q.

[0295] Dess-Martin pcriodinane (172 mg. 0.404 mmol) was added to a solution of 15-6 (90 mg. 0.162 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 1 h. A 1:1 sat. aq. NaHCO₃ solution-sat. aq. Na₂S2O3 solution was added. The mixture was stirred at r.t. for 30 mins and the layers were separated. The organic portion was washed with water, dried (NaaSOa), filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 50:50 to 10:90) afforded 15-7 as a pale yellow wax (70 mg. 78%). 'H NMR (400 MHz, CDC1₃) δ ppm 1.45 (s. 6 H), 3.83 (s. 3 H). 3.86 -3.92 (m, 2 H). 3.96 (s, 3 H), 4.27 (t, 7=5.0 Hz, 2 H). 4.52 (s. 2 H), 4.60 (s. 2 H), 5.11 (d, 7=4.5 Hz, 2 H), 6.91 (d.

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PCT/US2014/051642 <7=8.5 Hz. 2 H), 6.95 (d, .7=8.5 Hz, 1 H), 7.02 (s, 1 H), 7.32 (d, ,7=8.5 Hz, 2 H), 7.41 (dd, <7=8.3, 1.8 Hz, 1 H), 7.51 (d, <7=1.8 Hz, 1 H), 7.90 (s, 1 H).

[0296] A mixture of 15-7 (90.0 mg, 0.126 mmol), (3-chloro-4fluorophenyl)boronic acid (55.0 mg. 0.316 mmol), Pd(dppf)C12 (6.0 mg. 0.008 mmol) and aq. Na2CO3 (2M solution. 190 uL. 0.378 mmol) in DCE (3 mL) was degassed and heated to 85°C. After 20 h, the volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 80:20 to 0:100) afforded the PMB-ether (51 mg). The PMB-ether was dissolved in DCM (1.5 mL) and treated with TFA (200 uL). The mixture was stirred at r.t. for 30 mins and quenched with 2M aq. NaOH solution. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried (Na^SOff filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 80:20 to 0:100) afforded 140 as a white solid (20 mg, 30% over two steps). 'H NMR (400 MHz. CDCI3) δ ppm UPLC/MS(ES⁺): m/z 529.15 [M+H]⁺.

[0297] Coupling of 15-7 with 7-fluoro-3-(tetramethyl-l,3.2-dioxaborolan-2-yl)-l{[2-(trimethylsilyl)ethoxy]-methyl}-lH-indole followed removal of all protecting groups (TFA-DCM) afforded 141 as an off-white solid (9% over two steps). UPLC/MS(ES⁺): m/z 534.33 [M+H]⁺.

EXAMPLE 15

Preparation of Compound 142

16-1 16-2

[0298] MeMgBr (0.7 mL, 2 mmol) was added dropwise to a stirred solution of 16-1 (700 mg, 0.3 mmol) in THF (5 mL) at -78°C. After 1 h, the mixture was allowed to warm to r.t. (approx. 2 h). The reaction was quenched with IN HC1 and extracted with

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EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4 and concentrated. The residue was purified by column on silica gel (PE:EA=10:l) to give 16-2 (350 mg. 41%).

[0299] A solution of 16-2 (350 mg. 0.96 mmol) in ammonia (6 mL) and EtOH (3 mL) was stirred at 90°C for 10 h. The solvent was removed and the crude product was used in next step without purification.

[0300] To a solution of 16-4 (73 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1 mL) was added HATU (152 mg. 0.4 mmol), and stirred at 40°C for 30 mins. Compound 163 (100 mg, 0.33 mmol) was added. The mixture was stirred at 40°C for 10 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was washed with brine, dried over Na₂SO4, and concentrated. The crude product was purified by prep-HPLC to give 142 (60 mg, 39%). +ESI-MS:m/z 488.9 [M +Na]⁺.

EXAMPLE 16

Preparation of Compound 143

[0301] To a solution of 17-2 (132 mg, 0.4 mmol) in DIPEA (0.2 mL) and DMF (1 mL) was added IIATU (152 mg, 0.4 mmol), and the mixture stirred at 40°C for 30 mins. Compound 17-1 (100 mg, 0.33 mmol) was added. The mixture was stirred at 40°C for 10 h. The mixture was diluted with water and extracted with EtOAc. The organic layers was washed with brine, dried over Na₂SO4, and concentrated. The crude product was purified by column on silica gel (PE:EA=1:1) to give 17-3 (60 mg. 32%).

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PCT/US2014/051642 [0302] To a solution of 17-3 (60 mg, 0.1 mmol) in DCM (2 mL) and H?O (0.2 mL) was added DDQ (45 mg, 0.2 mmol). The mixture was stirred for 2 h. at r.t. The mixture was dissolved in DCM (30 mL). The solution was washed with sat. NaHCO₃. dried over

Na2SO4, and concentrated. The residue was purified by prep-HPLC to give 143 (30 mg.

60%). +ESI-MS:m/z 496.9 [M+H]⁺.

EXAMPLE 17

Preparation of Compound 144

H

NBS

CH₂CI₂

Br

Br

Mel _χ

DMF. K₂CO₃

18-2

18-1

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[0303] To a solution of 4(5)-methylimidazole (2 g, 24 mmol) in CH7CI2 (150 mL) was added bromine (2.5 mL, 48 mmol) at 0^l’C. The solution was stirred for 1 H at r.t. The product was filtered and partitioned between EA and sat. NaHCO.3. The product was precipitated from MeOH/CH₂Cl₂ to provide 18-1 (4.31 g, 75 %). 'H NMR (400 MHz. DMSO-d₆): δ 2.06 (s, 3H).

[0304] To a solution of 18-1 (3.6 g, 15 mmol) and K2CO3 (4.1 g, 30 mmol) in DMF (18 mL) was added iodomethane (1.4 mL, 23 mmol) at 25^1>C. The solution was stirred for 15 h. The mixture was poured into water and extracted with EA The combined organic phase was dried over anhydrous NibSCL, and the residue was purified by chromatography on silica gel (EA/hexane) to give 18-2 (1.6 g, 41%). 'H NMR (400 MHz, CDC1₃): δ 3.52 (s. 3H). 2.21 (s, 3H).

[0305] To a solution of methyl vanillate (7.06 g, 39 mmol) and K2CO3 (10.7 g, 78 mmol) in DMF (25 111L) was added l-bromo-2-fluoroethane (4.3 mL, 58 mmol) at 25°C. The solution was stirred for 2 days. The mixture w^?as poured into water and extracted with EA. The combined organic layers were dried over anhydrous Na2SC>4, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 18-3 (8.92 g, 103 %).). 'H NMR (400 MHz. CDCI3): δ 7.63 (dd. J=2.15. 8.41, IH). 7.55 (d. J=8.41, IH), 4.724.86 (m. 2H). 4.27-4.35 (m, 2H), 3.90 (s. 3H), 3.88 (s, 3H).

[0306] To a solution of 18-3 (8.92 g. 39 mmol) in MeOH (150 mL) was added 2 N NaOH (40 mL. 78 mmol). The solution was stirred for 2 h at 70°C. The mixture was concentrated, acidified with 2N HC1 and extracted with EA to provide 18-4. (5.0 g. 30 %). 'H NMR (400 MHz. DMSO-d₆): δ 7.47 (dd, J=1.96, 8.41, IH), 7.38 (d, J=1.96, IH), 6.99 (d, J=8.41. IH), 4.61-4.76 (m. 2H). 4.17-4.27 (m, 2H).

[0307] To a solution of 18-4 (3.07 g, 14.3 mmol), glycine methyl ester HC1 salt (3.6 g, 29 mmol), HATU (6.5 g, 17 mmol) in DMF (15 mL) was added DIEA (10 mL, 57 mmol). The solution was stirred for 18 h at r.t. The mixture was diluted with EA. The

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PCT/US2014/051642 organic phase was washed with water, IN HC1, NaHCO₃ and brine, dried over anhydrous

NaaSCU, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 18-5 (2.02 g, 51%). 'H NMR (400 MHz, CDC1₃): δ 7.43 (d, .1=2.15,

IH), 7.30 (dd, .1=2.15, 8.42), 6.90 (d, J-8.42. IH). 6.57 (br. t. IH). 4.72-4.85 (m, 2H), 4.224.35 (m, 2H), 4.25 (d, J= 5.08, 2H) 3.85 (s, 3H), 3.79 (s. 3H).

[0308] To a solution of 18-5 (2.02 g, 7.1 mmol) in MeOH (50 mL) was added 2 N NaOH (10 mL. 20 mmol). The solution was stirred for 2 h at r.t. The mixture was concentrated, acidified with 2N HC1 and extracted with EA to provide 18-6. (1.38 g, 72 %). ‘H NMR (400 MHz, CD₃OD): δ 7.49 (m, 2H), 7.04 (d, J=8.42. IH). 4.62-4.85 (m. 2H). 4.254.34 (m, 2H), 4.08 (s. 2H), 3.90 (s, 3H).

[0309] To a solution of 18-6 (0.52 g. 1.9 mmol). N.O-dimethylhydroxylamine hydrochloride (0.23g. 3.8 mmol), EDCI (0.38g. 2.3 mmol) in DMF (3 mF) was DTEA (1.0 mF. 5.8 mmol). The solution was stirred for 2 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HC1, NaHCO₃ and brine, dried over anhydrous Na₃SO4, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 18-7 (0.28 g. 47%). 'H NMR (400 MHz. CDC1₃): δ 7.43 (d, .1=1.96, IH), 7.33 (dd, J=1.96, 8.22. IH), 6.90 (d, J=8.22, IH). 4.71-4.84 (m. 2H), 4.26-4.36 (m. 4H), 3.91 (3, 3H), 3.76 (s. 3H), 3.25 (s. 3H).

[0310] Isopropylmagnesium chloride (2.0M. 0.48 mL, 0.95 mmol) was added dropwise to a solution of 18-7 (0.12 g. 0.38 mmol) and 18-2 (0.13 g. 0.50 mmol) in THE (1.0 mL). The solution was stirred for 2 h at r.t. The reaction was quenched with IN HC1, diluted with EA and washed with brine. The organic solution was filtered to 18-8 (0.030 g. 20%). 'H NMR (400 MHz, CDC1₃): δ 7.49 (d, J =2.15, IH), 7.38 (dd, .1=2.15, 8.21, IH), 7.03 (t, .1=5.09, IH), 4.93 (d. .1=5.09, 2H), 4.74-4.96 (m, 2H), 4.28-4.37 (m, 2H), 3.96 (s, 3H), 3.93 (s, 3H), 2.22 (s, 3H).

[0311] A solution of 18-8 (30 mg. 0.070 mmol). 3-chloro-4-fluorophenylboronic acid (24 mg, 0.14 mmol), potassium acetate (21 mg. 0.21 mmol) and Pd(dppf)Cl₃ (10 mg. 0.014 mmol) was heated under microwave irradiation for 1 h at 110°C. The mixture was concentrated and purified by chromatography on silica gel (EA/hexane) to give 18-9 (24 mg. 72%). LCMS: m/z 478.10 [M+H]⁺.

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PCT/US2014/051642 [0312] Methylmagnesium bromide (0.33 mL. 0.46 mmol) was added to a solution of 18-9 (22 mg. 0.046 mmol) in THF (1.0 mL). The mixture was stirred for 2 h at r.t., and then quenched with IM HCI. The mixture was extracted with EA, washed with brine, dried and concentrated. The residue purified by reverse phase HPLC to give 144 (3.8 mg, 17%).

LCMS: m/z 494.15 [M+H]⁺.

EXAMPLE 18

Preparation of Compound 145

[0313] To a solution of 4(5)-methylimidazole (2 g. 24 mmol) in CH2CI2 (150 mL) was added bromine (2.5 mL, 48 mmol) at 0°C. The solution was stirred for 1 H at r.t. The product was filtered and partitioned between EA and sat. NaHCOj. The product was precipitated from MeOH/CHiCL to provide 19-1 (4.31 g. 75 %). 'H NMR (400 MHz, DMSO-d₆): 5 2.06 (s, 3H).

[0314] To a solution of 19-1 (3.6 g, 15 mmol) and K2CO3 (4.1 g, 30 mmol) in DMF (18 mL) was added iodomethane (1.4 mL, 23 mmol) at 25°C. The solution was stirred for 15 h. The mixture was poured into water and extracted with EA The combined organic phase was dried over anhydrous Na2SC>4, and the residue was purified by chromatography on silica gel (EA/hexane) to give 19-2 (1.6 g, 41%). 'Η NMR (400 MHz, CDCI3): δ 3.52 (s. 3H), 2.21 (s. 3H).

[0315] Compound 145 was prepared using iodoethane and closely following the procedure for preparing of 144. LCMS: m/z 476.10 [M+H]⁺.

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EXAMPLE 19

Preparation of Compound 146

[0316] To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g. 1.6 mmol). 20-1 (0.485 g, 1.6 mmol), HATU (0.75 g. 2.0 mmol) in DMF (3 mF) was added DIEA (0.71 mL. 4.1 mmol). The solution was stirred for 18 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HC1. Nal ICO; and brine, dried over anhydrous Na₂SO4. and concentrated. The residue was purified by chromatography on silica gel (MeOH/CH₂Cl₂) to give 20-2 (0.176 g, 51%). 'H NMR (400 MHz, CDC1₃): δ 7.99 (dd. J=2.15, 7.24, IH), 7.81-7.85 (m, IH), 7.75 (d. J=8.02, IH), 7.37-7.42 (m. 2H), 7.26-7.27 (m, IH), 7.25 (t, J=8.71. IH), 6.93 (dd, J=1.96, 8.02), 6.83-6.86 (m, IH), 4.97-4.99 (m, IH), 3.99-4.13 (m, IH). 3.90 (s, 3H), 3.89 (s. 3H), 3.54-3.72 (m, IH).

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PCT/US2014/051642 [0317] A solution of 20-2 (2> mg, 0.045 mmol), pyridine-3-boronic acid (11 mg, 0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)C12 (6 mg, 0.009 mmol) in DME (0.5 mL) and H?O (0.05 mL) was heated under microwave irradiation for 1 h at 110⁽’C. The mixture was concentrated and purified by chromatography on silica gel (MeOH/CFECE) to give 20-3 (22 mg, 88%). 'H NMR (400 MHz, CDC1₃): δ 8.74-8.90 (br. s. 1H). 8.60-8.72 (br. s, 1H), 8.00, dd, >2.15. 7.24). 7.85-7.88 (m, 2H), 7.34-7.45 (m, 5H). 7.17. (t. >8.80. 1H). 6.94-6.97 (m, 1H), 4.98-5.01 (m. 1H), 4.00-4.09 (m. 1H), 3.88 (s. 3H), 3.82 (s, 3H0. 3.68-3.75 (m, 1H).

[0318] Dess-Martin periodinane (25 mg. 0.061 mmol) was added to a solution of 20-3 (22 mg. 0.043 mmol) in CH2CL. and stirred for 2 h. The mixture was diluted with CH2CI2, washed with sat. Na2CO₃, and brine, dried over MgSO|. and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EA/hexane) to give 20-4 (6.1 mg, 28%). LCMS: m/z 506.10 [M+H]⁺.

[0319] Methylmagnesium bromide (1.4 M in THF, 0.39 mL. 0.39 mmol) was added to a solution of 20-4 (20 mg. 0.039 mmol) in EHF (1.0 mL) and stirred for 2 h. The mixture was diluted with quenched with IN HC1 and extracted with EA. The organic extracts were washed with brine, dried over MgSO₄. and concentrated under reduced pressure. The crude product purified by reverse phase HPLC to provide 146 (0.9 mg, 4%). LCMS: m/z 522.15 [M+H]⁺.

Cl [0320] Compound 147 was prepared using pyridine-4-boronic acid pinacol ester in the Suzuki reaction and by following a synthetic route, which closely follows that described for preparation of 146. LCMS: m/z 522.15 [M+Hj¹.

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EXAMPLE 20

Preparation of Compound 148

148 [0321] To a solution of 21-1 (100 mg, 0.549 mmol), HATU (208 mg, 0.549 mmol) and DIPEA (142 mg, 1.1 mmol) in anhydrous DMF (2 mL) was added 21-2 (100 mg 0.347 mmol) at 25°C. The solution was stirred for 10 h at this temperature and then diluted with 1.0 N aqueous NalICCL solution (2 x 40 mL). extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous NtoSCL, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 21-3 (100 mg, 40.3%). +ES1-MS: m/z 433.1 [M+H]⁺.

[0322] To a solution of 21-3 (100 mg, 0.22 mmol) in THF (2 mL) were added Ag2O (20 mg) and CH3I (100 mg. 0.72 mmol). The mixture was stirred for 15 h at 40°C. The solid was removed, and the filtrate was concentrated. The residue was purified by prepHPLC (FA) to give 148 as a white solid (40 mg, 38.8 %). +ES1-MS: m/z 466.9 [M+H]⁺.

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EXAMPLE 21

Preparation of Compound 149

22-1 22-2

O

[0323] To a solution of 22-1 (1.1 g, 3.1 mmol) in DCM (3 mL) was added DAST (1.4 g; 8.7 mmol). The solution was stirred at r.t. for 1 h with TLC monitoring. The reaction was quenched with aq. NaHCOs at 0°C and extracted with DCM. The combined organic solution was dried over anhydrous MgSCfi, and evaporated under reduced pressure. The residue was purified on a silica gel column (PE:EA=20:l to 6:1) to give 22-2 (0.8 g).

[0324] To a solution of 22-2 (0.8 g, 2.2 mmol) in DMSO (5 mL) was added NaNi (300 mg 4.6 mmol). The solution was stirred at 60°C for 3 h with LCMS monitoring. The reaction was quenched with aq. NaHCOj and extracted with EA. The combined organic solution was dried over anhydrous MgSO4. and evaporated under reduced pressure to give crude 22-3 (0.7 g), which was used in next step directly without purification.

[0325] To a solution of 22-3 (0.7 g, 2.1 mmol) in EtOH (10 mL) and HC1 (2 drops. 1.0 N) was added Pd/C (10%. 400 mg) under No. The suspension was degassed under vacuum and purged with Ho 3 times. The mixture was stirred under Ho (40 psi) at r.t. for 1 h. The suspension was filtered through a pad of Celite and the pad cake was washed w'ith EtOH. The combined filtrates were concentrated to give crude 22-4 (0.4 g) used for next step directly without purification

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PCT/US2014/051642 [0326] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (212 mg, 1.0 mmol), IIATU (570 mg, 1.5 mmol) and DIPEA (322 g, 2.5 mmol) in anhydrous DCM (5 mL) was added 22-4 (298 mg, 1.0 mmol) at 25°C. The solution was stirred for 3 h. at this temperature, diluted with 1.0 N aqueous NaHCOj solution, and extracted with DCM. The combined organic layers were washed by brine, dried over anhydrous Na^SCfi, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 149 (180 mg) as a white solid. +ESI-MS::m/z 493.0 [M+H]⁺.

10327] Compound 150 was prepared using 6-(2-bromo-1,1 -difluoroethyl)-2-(3 chloro-4-fluorophenyl)-3-methoxypyridine, and by following a synthetic route, which closely follows that described for preparation of 149. +ES1-MS: :m/z 510.9 [M+H]⁺.

EXAMPLE 22

Preparation of Compound 151

Cl

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PCT/US2014/051642 [0328] To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) in toluene (2 mL) was added pyrrolidinone (150 mg. 1.7 mmol), potassium phosphate (0.55 g. 2.2 mmol), xantphos (25 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40 mg, 0.43 mmol). The mixture was heated at 110°C for 3 h. The mixture was then diluted with EA. The organic phase was washed with water, IN HCL NaHCO₃ and brine, dried over anhydrous NaNCf, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 23-1 (0.178 g, 83%). LCMS: m/z 478.10 [M+H]⁺.

[0329] To a solution of 23-1 (0.178 g. 0.72 mmol) in methanol (6 mL) was added NaOH (2.0 M, 2.0 mL) at 25°C. The solution was stirred for 15 h, acidified with 2N HC1 and extracted with EA. The combined organic phase was dried over anhydrous Na2SC>4 to give 23-2 (0.152 g. 90%). 'H NMR (400 MHz. CDC1₃): δ 7.52 (dd, >1.77. 8.22 Hz, IH). 7.51 (d. >1.77 Hz, IH), 7.30 (d. >8.22 Hz, IH), 3.82 (s. 3H), 3.75 (t, >7.04 Hz. 2H). 2.55 (t. >8.02 Hz. 2H), 2.0-2.3 (m, 2H).

[0330] To a solution of 23-2 (0.152 g. 0.65 mmol). 23-3 (0.19 g, 0.65 mmol), HATU (0.37 g, 0.97 mmol) in DMF (1 111L) was added DIEA (0.23 mL. 1.3 mmol). The solution was stirred for 2 h at r.t. The mixture was diluted with EA. The organic phase was washed with water. IN HC1. NaHCCf and brine, dried over anhydrous NaiSCfi. and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 23-4 (0.172 g, 51%). LCMS: m/z 478.10 [M+H]⁺.

[0331] Dess-Martin periodinane (220 mg, 0.50 mmol) was added to a solution of 23-4 (172 mg, 0.34 mmol) in CH₂C1₂, and the mixture was stirred for 2 h. The mixture was diluted with CH₂C1₂ and washed with sat. Na₂CO₂,. and brine, dried over MgSCfi, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (EA/hexane) to give 23-5 (77 mg, 45%) as white solid. LCMS: m/z 512.10 [M+H]⁺.

[0332] Methylmagnesium bromide (1.0 mL, 1.4 mmol) was added to a solution of 23-5 (72 mg. 0.14 mmol) in THF (1.0 mL). The mixture was stirred for 2 h at r.t.. and then quenched with IN HCL The mixture was extracted with FA. washed with brine, dried and concentrated. The residue purified by reverse phase HPLC to give 151 (6.5 mg. 17%) as white solid. LCMS: m/z 528.15 [M+H]⁺.

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EXAMPLE 23

Preparation of Compound 152

[0333] To a stirring mixture ol'24-1 (44 mg, 0.197 mmol) in DMF were added HATU (83 mg, 0.218 mmol) and DIPEA (51 mg, 0.4 mmol). The mixture was stirred at r.t. for 10 mins and a solution of 2-amino-l-(6-bromo-5-methoxypyridin-2-yl)ethan-l-ol was added. The mixture was stirred at r.t. for 1 h. diluted with EtOAc and quenched with a sat. NaHCOa solution. The mixture was stirred at r.t. for 10 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na^SO-i). fdtered and concentrated under reduced pressure. The crude product was purified via silica gel chromatography to afford 24-2. LCMS: m/z 451.05 [M+H]⁺.

[0334] To a stirring mixture of 24-2 (28 mg, 0.062 mmol) in DME/water (10:1, 2.2 mE) were added CS2CO3 (60 mg, 0.19 mmol). PdCFdppf/lO mg. 0.012 mmol), and (3chloro-4-tluorophenyl)boronic acid (11 mg. 0.062 mmol). The mixture was stirred under microwave conditions at 110°C for 1 h. The crude product mixture was cooled to r.t. and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography to afford 152. LCMS: m/z 501.15 [M+H]⁺.

[0335]

Compounds

153 and 154 were prepared using commercially available benzoic acids and 2-amino-l-(6-bromo-5-methoxypyridin-2-yl)ethan-l-ol in 2 or 3 steps, and

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PCT/US2014/051642 by following a synthetic route, which closely follows that described for preparation of the compound of Example 23. 153: LCMS: m/z 497.05 [M+I I]' . 154: LCMS: m/z 475.10 [M+H]⁺.

EXAMPLE 24

Preparation of Compound 155

Br„CN

K₂CO₃, CH₃CN

NaOH

MeOH

25-3

155 [0336] To a solution of 25-1 (1.82 g. 10 mmol) and K₂CO₃ (2.76 g, 20 mmol) in CH₃CN (20 mL) at r.t. was slowly added 2-bromoacetonitrile (2.4 g, 20 mmol). The mixture was heated to reflux and stirred for 15 h. The solvent were removed under reduced pressure. Purification by column chromatography on silica gel (PE:EA=3:1) provided 25-2 (2 g, 90%).

[0337] To a solution of 25-2 (2.21 g, 10 mmol) in methanol (10 mL) was added NaOH aqueous (10 mL. IM). The mixture was stirred for 4 h at 60^l’C. The solution was cooled to r.t., acidified to pH=4 using IN HC1 solution and extracted with EtOAc. The organic phase was dried with anhydrous Na₂SO4 and concentrated under reduced pressure to provide 25-3 (1.1 g. 50%).

[0338] To a solution of 25-3 (226 mg. 0.1 mmol) in DMF (3 mL) were added HATU (570 mg. 1.5 mmol) and DIPEA (387 mg. 3 mmol) at r.t. The solution was stirred for 10 mins at r.t. Compound 25-4 (287 mg, 1 mmol) was added and stirred for 1 h. The solution was extracted with EtOAc and washed with H₂O. The organic phase was

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PCT/US2014/051642 concentrated and purified by prep-TLC to give 155 (200 mg, 40%). +ES1-MS: m/z 495.9 [M+II]⁺.

EXAMPLE 25

Preparation of Compound 156

F

MeONH₂.HCI pyridine

EtOH, 80 oC [0339]

Ό

O

To a stirring mixture of N-(2-(6-(7-fluorobenzo[b]thiophen-3-yl)-4niethylpyridin-2-yl)-2-oxoethyl)-3.4-dimethoxybenzamide (20 mg, 0.043 mmol) in EtOH (0.25 mL) were added methoxy amine hydrochloride (4 mg. 0.048 mmol) followed by an addition of pyridine (34 mg. 0.43 mmol). The mixture was heated at 80°C for 30 mins and then cooled to r.t. The mixture was concentrated under reduced pressure. The crude mixture was purified via prep-HPLC to afford 156. LCMS: m/z 494.10 [M+H]⁺.

[0340] Compound 157 was prepared using N-(2-(6-(7-fluorobenzo[b]thiophen-3yl)pyridin-2-yl)-2-oxoethyl)-3.4-dimethoxybenzamide and hydroxylamine hydrochloride, and by following a synthetic route, which closely follows that described for preparation of 156. LCMS: m/z 466.25 [M+H]⁺.

EXAMPLE 26

Preparation of Compound 158

[0341] To a stirring mixture of 158 (20 mg, 0.036 mmol) in THE (1 mL) were added bis(tri-/e/7-butylphosphine)palladium(0) (3.6 mg, 0.008 mmol), and a solution of MeZnCl in THE (0.055 mL. 0.11 mmol). The mixture was stirred under microwave

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PCT/US2014/051642 condition at 100°C for 1 h. The mixture was cooled to r.t.. diluted with EtOAc and slowly quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 20 mins and then the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na?SO4). filtered and concentrated under reduced pressure. The crude product mixture was purified via silica gel column to afford 159 as a colorless oil. LCMS: m/z 495.1 [M+H]⁺.

EXAMPLE 27

[0342] To a stirring mixture of 26-1 (50 mg, 0.082 mmol) in MeOH (1 mL) were added anionium acetate (94 mg, 1.23 mmol), NaCNBH.3 (7.7 mg. 0.12 mmol). The mixture was heated at 70^l’C for 1 h and then cooled to room temperture. The mixtue was diluted wtih EtOAc and slowly quenched with a sat. NII4CI solution. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na?SO4). filtered and concentrated under reduced pressure. The crude product mixture was purified via silica gel chromatography to afford 26-2. The PMB ether was removed using TFA in DCM at r.t. The crude product was concentrated under reduced pressure and purified via prep-HPLC to afford 160 (3.1 mg) as a white solid. LCMS: m/z 490.15 [M+H]⁺.

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EXAMPLE 28

Preparation of Compound 161

[0343] To a solution of 3-methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (205 mg. 0.62 mmol ) in DMF (15 mL) were added DIPEA (320 mg, 2.48 mmol) and HATU (235.6 mg, 0.62 mmol). The mixture was stirred at r.t. for 30 mins, and 27-1 (195 mg, 0.62 mmol) was added. The mixture was stirred at r.t. overnight. The mixture was diluted with water and extracted with EA. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by column chromatography to give 27-2 (180 mg). +ESI-MS: m/z 631.1 [M+H]⁺.

[0344] Compound 27-2 (180 mg, 0.286 mmol) was dissolved in TFA/DCM (10 mL). The mixture was stirred at r.t. for 1 h (monitored by TLC). The mixture was extracted with EA, and washed with a sat. NaHCO₃ solution. The organic layer was dried over sodium sulfate, and concentrated in vacuum to give the crude product, which was purified by prepHPLC to give 161 (50mg) as a white solid. +ESI-MS: m/z 511.1 [M+H]⁺.

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EXAMPLE 29

Preparation of Compound 162

[0345] A solution of 28-1 (2.59 g, 0.01 mol) in NHs/MeOH (20 mL) was stirred at r.t. for 30 mins. The solvent was removed by rotary⁷ evaporator. The residue. 28-2. was used in next step.

[0346] A mixture of 28-2 (2.44 g, 0.01 mol) 28-3 (2.73 g, 0.01 mol) and AgSbF<, (5.14 g, 0.015 mol) in DME (20 mF) was stirred for 2 h at 120^l’C under microwave irradiation. The mixture was filtered. The filtrate was concentrated by rotary evaporator to give crude 28-4 (5 g), which was used in next step without further purification.

[0347] To a solution of 28-4 (5 g) in EtOAc (10 mF) was added HCl-EtOAc (30 mF). The solution was stirred for 10 h. The solvent was concentrated by rotary evaporator. The product was purified by prep-HPEC to give 28-5 (250 mg). ESI-MS: m/z 278.8 [M+H]⁺.

[0348] To a solution of 28-5 (145 mg, 0.8 mmol) in DMF (10 mF) was added HATU (343 mg, 0.9 mmol). DIEA (155 mg. 1.2 mmol), and stirred for 5 mins. 3,4dimethoxybenzoic acid (250 mg. 0.8 mmol) was added and the mixture was stirred for 5 h. Water (100 mL) was poured into the solution, and a solid precipitated. The solid was purified by silica column chromatography (PE:EA=1:1) to give 162 (158 mg, 45%). ESIMS: m/z 442.9 [M+H]⁺.

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EXAMPLE 30

Preparation of Compound 163

29-2 29-3

29-4

163 [0349] A 50 mL three-necked round bottle flask was charged with a solution of 2,6-dibromopyridine (1.15 g, 5 mmol, 5.0 eq.) in THF under nitrogen. The solution was cooled to -78°C, and w-BuLi (2 mL, 5 mmol. 5.0 eq.) was added dropwise. After addition, the mixture was stirred for 30 mins. A solution of 29-1 (115 mg, 1.0 mmol, 1.0 eq.) (prepared according to Wuitschik et al., J. Med. Chem. (2010) 53(8):3327-3246. which hereby is incorporated by reference for the limited purpose of preparing 29-1) in THF (3~5 mL) was added dropwise. After addition, the mixture was stirred for 30 mins. The reaction was quenched with sat. NH4CI. and the mixture was extracted by EA (3 x 10 mL). The combined organic phase was concentrated to dryness, and the residue was purified by prepTLC to give 29-2 as a yellow oil (80 mg). 'H-NMR (400MHz, CDCI3), δ = 7.67 - 7.60 (m, IH), 7.55 (d. J=7.5 Hz, IH), 7.44 (d. J=8.0 Hz, IH), 5.23 (s. 2H), 4.99 (d. J=7.0 Hz. 2H), 4.89 (d, J=7.0 Hz, 2H).

[0350] A 50 mL round bottom flask was charged with a mixture of 29-2 (0.4 g. 1.46 mmol), boric ester (0.6 g. 2.16 mmol. 1.5 eq.). Pd(dppf)CL (107 mg, 0.146 mmol. 0.1 eq.) and Na₂CO₃ (320 mg, 3.0 mmol, 3.0 eq.) in dioxane/H₂O (10 mL/2 mL). The mixture was degassed and refilled with nitrogen. The mixture was heated to reflux overnight. The mixture was cooled to r.t. and concentrated to dryness. The residue was purified by column

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PCT/US2014/051642 on silica gel (5-10% EA in PE) to give 29-3 as a pink oil (0.44 g, 87% yield). 'H-NMR (400MHz, CDC1.0, δ = 8.02 (d, .1=8.5 Hz, IH), 7.92 (t, .1=7.8 Hz, IH), 7.81 (s, IH), 7.67 (dd, .1=7.8, 14.3 Hz. 2H), 7.42 (dt, .1=5.5, 8.0 Hz, IH), 7.16 - 7.07 (m, IH), 5.33 (s, 2H), 5.10 (d,

J=7.0 Hz, 2H), 5.00 (d, .1=6.5 Hz, 2H).

[0351] A 250 mL round bottom flask was charged with a solution of 29-3 (0.4 g, 1.17 mmol) in EtOH (100 mL) and Pd/C (0.2 g). The mixture was stirred under hydrogen balloon overnight. The mixture was filtered, and concentrated to dryness. Crude 29-4 was used in the next step without further purification.

[0352] To a solution of 29-4 (270 mg. 0.86 mmol, 1.0 eq.), acid (313 mg, 0.942 mmol. 1.1 eq.) and D1EA (0.33 g, 3.0 eq.) in DMF (10 mL) was added HATU (360 mg, 0.942 mmol. 1.1 eq.), and the mixture was stirred at r.t. overnight. The mixture was diluted with EA and water. The organic phase was washed with brine, dried over anhydrous MgSO |. and concentrated to dryness. The residue was purified by silica gel column (60% EA in PE) to give 29-5 as a pale yellow oil (0.4 g. 74%).

[0353] To a solution of 29-5 (0.35 g) in DCM (25 mL) was added TFA (5 mL), and the mixture was stirred at r.t. for 10 mins. The mixture was neutralized with sat. Na^COa solution. The organic phase was concentrated and purified by prep-TLC to give 163 as a white solid (70 mg). +ES1-MS: m/z 509.0 [M+H]⁺.

EXAMPLE 31

[0354] To a solution of 30-1 (190 mg. 0.30mmol) in THF (5 mL) was added

NaEII i (20 mg. 0.6 mmol) at r.t. MeOH (ImL) was added, and the mixture was stirred at

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20⁽’C for 1 h. The residue was purified by column chromatography on silica gel (PE) to provide 30-2 (190 mg, 99 %).

[0355] To a solution of 30-2 (190 mg, 0.3 mmol) in DCM (3 mL) was added TFA (0.5mL) and HoCL (0.2 mL, 30%. 2eq). and the mixture was stirred for 30 mins. The mixture was neutralized with a sat. NaHCCfi solution, and extracted with DCM (3 x lOmL). The solution was concentrated to give 164 in crude form (200 mg), +ESI-MS: m/z 625.0 [M+H]⁺.

EXAMPLE 32

Preparation of Compound 165

-O

[0356] Compound 31-2 (106 mg, 0.5 mmol). 31-1 (140 mg, 0.5 mmol) and triethylamine (1 mmol) were dissolved in DMF (5 mL). HATU (380 mg, 1 mmol) was added to the solution. After 15-30 mins, the mixture was treated with sat. NaCl solution (100 mL), and extracted with EtOAc (3 x 10 mL). The combined organic phase was washed with 2N HC1 solution and 5% NaHCOj solution. The organic layer were dried over anhydrous MgSO₄, and concentrated in vacuum to give the crude product. The crude product was purified by silica gel column chromatography eluting with EtOAc/PE (1/1) to give 165 as a white solid (24 mg. 10%). +ESI-MS: m/z 483.0 [M+H]⁺.

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EXAMPLE 33

solution of 32-1 (300 mg, 1.40 mmol) in dry DCM (6.5 mL). The mixture was stirred at r.t. for 1 h and quenched with a 1:1 mixture of 2M aq. Na^Ch solution and sat. aq. NaHCOj solution (10 mL). The mixture was stirred vigorously for 30 mins and the layers were separated. The organic portion was washed with brine, dried (Na2SC>4), filtered and concentrated under reduced pressure. The crude aldehyde was progressed to the next step without further purification. The aldehyde was dissolved in tert-butanol (21 mL). To the solution, 2-methyΊ-2-butene (1.13 mL, 13.5 mmol) and a solution of sodium chlorite (244 mg, 2.70 mmol) and sodium phosphate monobasic dihydrate (1.36 g, 8.70 mmol) in water (21 mL) were added. The mixture was stirred at r.t. for 18 h. Brine was added and the mixture was extracted 3 times with EtOAc. The combined organic portions were dried (Na2SO4) and filtered. The volatiles were removed under reduced pressure. Acid 32-2 (310 mg) was progressed to the next step without further purification. LJPLC/MS(ES⁺): m/z 228.07 [M+H]⁺.

[0358] 1.1 '-Carbonyldiimidazole (1.17 g. 7.21 mmol) was added to a solution of

32-2 (250 mg) in THF (9.6 mL). The mixture was stirred at r.t. for 30 mins and then

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PCT/US2014/051642 nitromethane (671 mg, 11.0 mmol) and potassium carbonate (608 mg, 4.40 mmol) were added. After 3 h, the volatiles were removed under reduced pressure. The residue was taken up with EtOAc. The organic portion was washed with water, dried with Na2SO4, filtered and concentrated under reduced pressure. Crude 32-3 (300 mg) was progressed to the next step without further purification. UPLC/MS(ES⁺): m/z 271.05 [M+H]⁺.

[0359] Methylmagnesium bromide (3M solution in Et20, 204 uL, 0.612 mmol) was added to a solution of 32-3 (300 mg) in THF (8 mL), which had been pre-cooled to 40°C. The mixture was stirred at -40°C for 1 h, allowed to reach r.t. and then quenched with IM aq. HCI solution. The aqueous portion was extracted twice with EtOAc. The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure. Crude 32-4 was progressed to the next step without further purification. UPLC/MS(ES⁺); m/z 287.10 [M+H]⁺.

[0360] NaBl 11 (52.0 mg. 1.38 mmol) was added to a solution of NiCL-bFLO (109 mg, 0.460 mmol) in MeOH (10 mL). After 30 mins, nitro-derivative 32-4 (250 mg) dissolved in MeOH (2 mL) was added, followed by additional solid NaBHq (70 mg). The reaction was monitored by LJPLC. When complete, the mixture was filtered through a pad of celite and the organic portion was concentrated under reduced pressure. Crude 32-5 (235 mg) was progressed to the next step without further purification. UPLC/MS(ES⁺): m/z 257.17 [M+H]\ [0361] A mixture of 32-5 (235 mg). 3-mcthoxy-4-{2-[(4methoxyphenyl)methoxy]ethoxy}benzoic acid (365 mg. 1.10 mmol), EDC (263 mg. 1.38 mmol), HOBT (186 mg, 1.38 mmol) and TEA (255 uL, 1.84 mmol) in DCM (8 mL) was stirred at r.t. for 3 h. The mixture was washed twice with IM aq. HCI solution. The organic portion was dried (bfeSCfi). filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc. 60:40 to 10:90) afforded 32-6 as an offwhite solid (60 mg, 12% starting from 32-1). UPLC/MS(ES⁺): m/z. 571.20 [M+H]⁺.

[0362] A mixture of 32-6 (60 mg. 0.100 mmol), (3-chloro-4-fluorophenyl)boronic acid (91.0 mg, 0.500 mmol). Pd(dppf)Cl2 (3.6 mg, 0.005 mmol) and aq. NaaCCh (2M solution, 0.500 mmol. 250 uL) in DCE (1 mL) was degassed and then stirred with heat to 85°C for 4 h. Water and DCM were added, and the layers were separated. The organic phase

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PCT/US2014/051642 was dried with NiySOa. filtered and evaporated. Chromatography of residue (cyclohexane:EtOAc, 100:0 to 20:80) afforded 32-7 (46 mg. 69%). UPLC/MS(ES⁺): m/z

665.47 [M+H]⁺.

[0363] A solution of 32-7 (46.0 mg. 0.069 mmol) in 10:1 DCM-TFA (1.1 mL) was stirred at room temperatire for 1 h. IM aq. NaOH solution was added and the mixture was stirred for 15 mins. The layers were separated. The organic portion was dried (Na?SO4). filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CHaCN. 100:0 to 50:50) to afford 166 as a white solid (racemic mixture. 18 mg, 33%). UPLC/MS(ES⁺): m/z 545.33 [M+H]⁺.

EXAMPLE 34

Preparation of Compound 167

[0364] To a stirring mixture of 33-1 (40 mg. 0.061 mmol) in THF (1.0 mL) at r.t. under argon was added a solution of MeMgBr (1.4 M) in THF (0.5 mL) dropwise. The mixture was reacted at r.t. for 1 h. The mixture was diluted with EtOAc and quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 10 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (NaaSOa), filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel column to afford 33-2 as a white solid. LCMS: m/z 669.1 [M+H]⁺.

[0365] To a stirring mixture of 33-2 (20 mg, 0.0299 mmol) in DCM (1.0 mL) at r.t. was added dropwise TFA (0.2 mL). The mixture was stirred at r.t. for 10 mins and then concentrated under reduced pressure. The crude product mixture was purified via prepHPLC to afford 167. LCMS: m/z 549.05 [M+H]⁺.

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EXAMPLE 35

[0366] To a stirring mixture of 2-bromothiazole (0.2 g. 1.22 mmol) in THF under Ar at -78°C was added dropwise a solution of n-BuLi (2.5 M) in hexane (0.49 mL. 1.22 mmol). The mixture was stirred at -78°C for 15 mins and then a solution of 34-1 (40 mg. 0.081 mmol) in THF (0.5 mL) was added. The mixture was stirred at -78°C for 1 h and then warmed to r.t. for 10 mins. The mixture was diluted with EtOAc and quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 10 mins and then the layers were separated. The aqueous layer was extracted with EtOAc (2x15 mL). The organic layers were dried (Na?SO₄). filtered and concentrated under reduced pressure. The crude mixture was purified via silica gel chromatography and further purified via prep-HPLC to afford 168 as a tan solid. LCMS: m/z 576.1 [M+H]⁺.

EXAMPLE 36

Preparation of Compound 169

169 [0367] To a solution of 34-2 (100 mg, 0.442 mmol), HATU (251 mg, 0.66 mmol) and DIPEA (170 mg, 1.32 mmol) in anhydrous DMF (2 mL) was added 34-3 (127 mg 0.442 mmol) at 25°C. The solution was stirred for 10 h at r.t. and then diluted with 1.0 N aqueous NaHCOa solution (2 x 40 mE), extracted with EA (2 x 20 ml.). The combined organic layers were washed with brine, dried over anhydrous Na2SO₄, and concentrated under reduced pressure. The residue was purified on a silica gel column to give 169 (120 mg, 54.8%). +ES1-MS: m/z 497.1 [M+H]⁺.

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EXAMPLE 37

Preparation of Compound 170

[0368] Compound 170 was prepared using 2.6-dichloro-3-methylpyridine, 2-(7fluorobenzo[b]thiophen-3-yl)-4,4,5,5-tetramethyl-1.3,2-dioxaborolane and 3,4dimethoxybenzoic acid, and by closely following a synthetic route, which closely follows that described for the preparation of 1. +ESI-MS:m/z 464.9 [M+H]^;.

EXAMPLE 38

Preparation of Compounds 171 and 172

[0369] To a solution of 3-methoxy-4-iodobenzoic acid (0.45 g. 1.6 mmol). 35-1 (0.485 g, 1.6 mmol), HATU (0.75 g. 2.0 mmol) in DMF (3 mL) was added DIEA (0.71 mL. 4.1 mmol). The solution was stirred for 18 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HC1. Nal ICO; and brine, dried over anhydrous Na₂SO₄, and concentrated. Phe residue was purified by chromatography on silica gel (MeOH/CH₂Cl₂) to give 171 (0.176 g, 51%). 'H NMR (400 MHz. CDCf): δ 7.99 (dd. >2.15. 7.24, IH). 7.81-7.85 (m, IH), 7.75 (d, >8.02, IH), 7.37-7.42 (m, 2H). 7.26-7.27 (m, IH), 7.25 (t. >8.71. IH), 6.93 (dd, >1.96. 8.02), 6.83-6.86 (m, IH), 4.97-4.99 (m, IH), 3.99-4.13 (m, IH). 3.90 (s, 3H), 3.89 (s. 3H), 3.54-3.72 (m, IH).

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PCT/US2014/051642 [0370] A solution of 171 (25 mg, 0.045 mmol), pyridine-3-boronic acid (11 mg, 0.09 mmol), potassium acetate (13 mg, 0.13 mmol) and Pd(dppf)C12 (6 mg, 0.009 mmol) in DME (0.5 mL) and I LO (0.05 mL) was heated under microwave irradiation for 1 h at 110⁽’C. The mixture was concentrated and purified by chromatography on silica gel (MeOH/CfUCE) to give 172 (22 mg. 88%). 'H NMR (400 MHz. CDC1₃): δ 8.74-8.90 (br. s. IH). 8.60-8.72 (br. s, IH), 8.00, dd, J=2.15. 7.24). 7.85-7.88 (m, 2H), 7.34-7.45 (m. 5H). 7.17. (t. .1=8.80. IH). 6.94-6.97 (m, IH). 4.98-5.01 (m. IH), 4.00-4.09 (m. IH), 3.88 (s, 3H), 3.82 (s, 3H0. 3.68-3.75 (m. IH).

EXAMPLE 39

Preparation of Compound 173

Cl

[0371] To a solution of methyl 3-methoxy-4-iodobenzoate (250 mg, 0.85 mmol) in toluene (2 mL) was added pyrrolidinone (150 mg, 1.7 mmol), potassium phosphate (0.55 g. 2.2 mmol), xantphos (25 mg, 0.43 mmol) and tris(dibenzylideneacetone)dipalladium(0) (40 mg. 0.43 mmol). The mixture was heated at 110°C for 3 h. The mixture was then diluted with EA. The organic phase was washed with water, IN HC1, NaHCO₃ and brine, dried over anhydrous AoSO i, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 36-1 (0.178 g. 83%). LCMS: m/z 478.10 [M+H]⁺.

[0372] To a solution of 36-1 (0.178 g, 0.72 mmol) in methanol (6 mL) was added NaOH (2.0 M, 2.0 mL) at 25‘’C. The solution was stirred for 15 h. acidified with 2N HC1 and extracted with EA. The combined organic phase was dried over anhydrous Na₃SO4 to give 36-2 (0.152 g. 90%). 'HNMR (400 MHz. CDCI₃): δ 7.52 (dd, .1=1.77. 8.22 Hz. IH). 7.51 (d.

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PCT/US2014/051642 .1=1.77 Hz, IH), 7.30 (d, .1=8.22 Hz, IH). 3.82 (s. 3H). 3.75 (t. .1=7.04 Hz, 2H), 2.55 (t, .1=8.02 Hz, 2H), 2.0-2.3 (m, 2H).

[0373] To a solution of 36-2 (0.152 g, 0.65 mmol), 36-3 (0.19 g, 0.65 mmol), HATU (0.37 g. 0.97 mmol) in DMF (1 mL) was added DIEA (0.23 mL, 1.3 mmol). The solution was stirred for 2 h at r.t. The mixture was diluted with EA. The organic phase was washed with water, IN HCI, NaHCCfi and brine, dried over anhydrous Na₂SO4, and concentrated. The residue was purified by chromatography on silica gel (EA/hexane) to give 173 (0.172 g. 51%). LCMS: m/z 478.10 [M+H]⁺.

EXAMPLE 40

Preparation of Compound 174

[0374] Addition of MeMgBr to 174-1 afforded 174 as a white solid (50%).

UPLC/MS(ES⁺): m/z 445.27 [M+H]⁺.

EXAMPLE 41

Preparation of Compound 175

175-1 ° ₁₇₅ [0375] Addition of MeMgBr to 175-1 afforded 175 as a white solid (10%). UPLC/MS(ES⁺): m/z 497.1 [M+H]⁺.

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EXAMPLE 42

OMe

OMe

HNRR-i

OMe

X = OH, NRR

OMe

[0376] Trimethylsulfoxonium iodide (1.19 g, 5.41 mmol) was added to a solution of potassium rm-butoxide (551 mg. 4.92 mmol) in DMSO (10 mL). The mixture was stirred at r.t. for 30 mins. A solution of N-{2-[6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl]2-oxoethyl} -3-methoxy-4- {2-[(4-methoxyphenyl)methoxy]ethoxy} benzamide (1, 3.00 g. 4.92 mmol) in DMSO (20 mL) was added. The mixture was stirred at r.t. for 10 mins. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried with NASOi and concentrated under reduced pressure to afford the crude epoxide 2 (3.34 g). Epoxide 2:UPLC/MS(ES⁺).· m/z 623.40 [M+H⁺]. With chromatography (cyclohexane-EtOAc. 75:25 to 50:50). epoxide 2 quantitatively rearranged to oxazoline 3 (1.92 g recovered from 3 g of crude 2). Oxazoline 3: UPLC/MS(ES⁺): m/z 623.29 [M+H⁺].

[0377] Method A: A mixture of epoxide 2 (100 mg, crude) and an amine (10 eq.) in MeOH (1 mL) was stirred at r.t. or heated to 100 °C. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in a 10:1 DCM:TFA mixture (2.2 mL). After 30 mins of stirring at r.t., a 2M aq. NaOII solution was added. The mixture was stirred at r.t. for 10 mins. The layers were separated, and the aqueous portion

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PCT/US2014/051642 extracted with DCM. The combined organic portions were dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue afforded the aminol.

[0378] Method B: A mixture of epoxide 2 (150 mg. crude), an amine (2 eq.) and K2CO3 (66.0 mg. 2 eq.) in DMF (2 mL) was stirred at 50 °C. When complete, the reaction was diluted with EtOAc. The organic portion was washed twice with water, dried with Na₂SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h, the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.

[0379] Method C: TEA (270 uL, 1.93 mmol) and MsCl (150 uL. 1.93 mmol) were added to a solution of 3 (600 mg, 0.964 mmol) in DCM (4 mL). The mixture was stirred at r.t. for 2 h. The mixture was poured into IM aq. HCT solution and extracted with DCM. The combined organic portions were dried with Na₂SC>4 and filtered. The volatiles were removed under reduced pressure to afford the crude mesylate 4. which was directly used in the next step. A mixture of 4 (80 mg) and an amine (50 uL) in MeOH (2 mL) was heated to 85 °C in a sealed vial. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in MeOH (1.5 mL) and treated with a 6M aq. HC1 solution (1.5 mL). The mixture was heated to 65 °C for 2 h. After cooling to r.t., the mixture was purified by reverse phase chromatography to afford the aminol.

[0380] Method D: A mixture of epoxide 2 (50 mg, crude) and an amine (10 eq.) was heated to 60 °C under microwave irradiation. When complete, the reaction was concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and treated with TFA (300 uL). After 1 h. the reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue afforded the aminol.

EXAMPLE 43

Preparation of Compound 176 oN

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PCT/US2014/051642 [0381] Epoxide 2 (200 mg, crude) was dissolved in a 1:1 MeOH:6M aq. HC1 solution (2 mL), and the mixture was stirred at 60 °C for 2 h. The mixture was basified with

6M aq. NaOH solution and purified by reverse phase chromatography (wateriCHsCN, 100:0 to 50:50) to afford 176 as an off-white solid (40.2 mg). UPLC/MS(ES⁺): m/z 521.10 [M+H]⁺.

EXAMPLE 44

Preparation of Compound 177

[0382]

Reaction of epoxide 2 with a 2M MeNlf-MeOEI solution followed by

PMB-group removal according to Method A afforded 177 as a white solid (13% over 3 steps). UPLC/MS(ES⁺): m/z 534.30 [M+H]⁺.

EXAMPLE 45

Preparation of Compound 178

[0383] Reaction of epoxide 2 with a 2M MejNH-MeOH solution followed by PMB-group removal according to Method A afforded 178 as a white solid (37% over 3 steps). UPLC/MS(ES⁺): m/z 548.30 [M+H]⁺.

EXAMPLE 46

Preparation of Compound 179

[0384] Reaction of epoxide 2 with a 7M NEf-MeOH solution followed by PMBgroup removal according to Method A afforded 179 as a white solid (24% over 3 steps). UPLC/MS(ES'): m/z 520.40 [M+Elj¹.

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EXAMPLE 47

Preparation of Compound 180

[0385] A solution of 179 (10.0 mg, 0.019 mmol) and triphosgene (5.0 mg. 0.019 mmol) in a 1:1 5% aq. Nal IC( )_;:\le()l I mixture (1 mL) was stirred and heated at 40 °C for 3 h. The volatiles were removed under reduced pressure to afford a 30:70 mixture of 180 and the corresponding methyl carbamate. This mixture was dissolved in DMF (0.5 mL) and treated with NaH (60% oil dispersion. 1 mg). After 30 mins, the reaction was quenched with MeOH, and the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (0.1% HCOOH:water-0.1% HCOOHrCHsCN, 100:0 to 30:70) to afford 180 as a white solid (4.0 mg. 39%). UPLC/MS(ES⁺): m/z 546.30 [M+H]⁺.

EXAMPLE 48

Preparation of Compound 181

[0386] Reaction of epoxide 2 with morpholine followed by PMB-group removal according to Method B afforded 181 as a white solid (10% over 3 steps). UPLC/MS(ES⁺): m/z 590.40 [M+H]⁺.

EXAMPLE 49

Preparation of Compound 182

[0387] A mixture of epoxide 2 (100 mg, crude), ketopiperazine (80 mg. 0.80 mmol) and K2CO3 (155 mg, 1.13 mmol) in DMF (2 111L) was stirred at 60 °C for 18 h. The

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PCT/US2014/051642 mixture was diluted with EtOAc, and the organic portion was washed with water (2x), dried with Na?SO4, filtered and concentrated under reduced pressure. The residue was dissolved in MeOH (2 mL) and treated with 3M aq. HC1 solution (500 uL). The mixture was heated to 80 °C and stirred at 80 °C for 30 mins. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (waler-CI LCN, 100:0 to 0:100) to afford 182 as a light yellow solid (14% over 3 steps). UPLC/MS(ES⁺): m/z 603.30 [M+H]⁺.

EXAMPLE 50

Preparation of Compound 183

n.n un n

[0388] Reaction of epoxide 2 with ketopiperazine followed by PMB-group removal according to Method B afforded 183 as a light yellow solid (10% over 3 steps).

UPLC/MS(ES⁺): m/z 621.40 [M+H]⁺.

EXAMPLE 51

Preparation of Compounds 184, 185 and 186

[0389] Reaction of epoxide 2 with pyrazole followed by PMB-group removal according to Method B afforded 184 as a racemic mixture (32% over 3 steps). This mixture was resolved by using a prep-HPLC separation [Chiralpak AD-H (25 x 2.0 cm), 5 μΜ; mobile phase: Ethanol + 0.1% isopropylamine 30%, flow rate: 46 mL/min, UV detection DAD 220 nm] to afford the two separated enantiomers 185 (tR= 11.0 min) and 186 (t«= 12.5 min). Analytical data for the single enantiomers: white solid. UPLC/MS(ES⁺): m/z 571.36 [M+H]⁺.

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EXAMPLE 52

Preparation of Compound 187

[0390] Reaction of mesylate 4 with pyrrolidine followed by PMB-group removal according to Method C afforded 187 as a white solid (55% over 3 steps). UPLC/MS(ES⁺): m/z 574.20 [M+H]⁺.

EXAMPLE 53

Preparation of Compound 188

[0391] Reaction of mesylate 4 with piperidine followed by PMB-group removal according to Method C afforded 188 as a white solid (6% over 3 steps). UPLC/MS(ES⁺): m/z 588.20 [M+H]⁺.

EXAMPLE 54

Preparation of Compound 189

[0392] Reaction of epoxide 2 with cyclopropylamine followed by PMB-group removal according to Method D afforded 189 as a white solid (11% over 3 steps). UPLC/MS(ES⁺): m/z 560.10 [M+H]⁺.

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EXAMPLE 55

Preparation of Compound 190

[0393] Reaction of epoxide 2 with 1-Boc-piperazine followed by PMB-group removal according to Method C afforded 190 (17% over 3 steps). UPLC/MS(ES⁺): m/z 589.30 [M+H]⁺.

EXAMPLE 56

|0394] Reaction of epoxide 2 with imidazole followed by PMB-group removal according to Method B afforded 191 as a white solid (12% over 3 steps). UPLC/MS(ES⁺): m/z 571.30 [M+H]⁺.

EXAMPLE 57

Preparation of Compounds 192 and 193

[0395] Reaction of epoxide 2 with lH-1.2,3-triazole followed by PMB-group removal according to Method B afforded compounds 192 (10% over 3 steps) and 193 (18% over 3 steps). 192: UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺. 193: UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺.

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EXAMPLE 58

[0396] Reaction of epoxide 2 with lH-1.2,4-triazole followed by PMB-group removal according to Method B afforded compound 194 (24% over 3 steps). UPLC/MS(ES⁺): m/z 572.30 [M+H]⁺.

EXAMPLE 59

Preparation of Compound 195

[0397] A mixture of epoxide 2 (80 mg. crude) and 7M NIL-MeOII (1.5 mL) in

McOH (2 mL) was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The resulting crude 195-1 was dissolved in DCM (1 mL) and treated with TEA (15 uL) and AcCl (11 uL). The mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. Deprotection of the PMB-ether using TFA:DCM afforded 195 as a white solid (7% overall). UPLC/MS(ES⁺): m/z 562.30 [M+H]⁺.

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EXAMPLE 60

Preparation of Compound 196

Boc

I

[0398] /7-BuLi (1.6M solution in hexanes. 650 pL, 1.04 mmol) was added to a suspension of tert-butyl 3-oxopiperazine-l-carboxylate (160 mg. 0.800 mmol) in dry THF (2 mL), which had been pre-cooled to 0 °C. The mixture was stirred for 5 mins at 0 °C and then warmed to r.t. After 5 mins, a solution of epoxide 2 (200 mg, crude) in THF (1 mL) was added. The mixture was heated to 50 °C and stirred at 50 °C for 12 h. Water and EtOAc were added. The layers were separated, and the aqueous portion was extracted with EtOA. The combined organic portions were dried with Na2SO4 and filtered. The volatiles were removed under reduced pressure. The crude 6 was dissolved in MeOH (5 mL) and treated with 6M aq. HCI solution (2 mL). The mixture was heated to 60 °C and stirred at 60 °C for 1.5 h. A majority of the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (waterCHjCN 100:0 to 40:60) to afford 196 as a white solid (31 mg, 16% over 3 steps). LJPLC/MS(ES⁺): m/z 603.30 [M+H]⁺.

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EXAMPLE 61

Preparation of Compound 197

[0399] Bromo(ethynyl)magnesium (4.90 mL, 2.46 mmol) was added to a solution of 1 (300 mg, 0.493 mmol) in THF (15 mL), which had been warmed to 55 °C. The mixture was stirred for 30 mins and quenched with sat. aq. NH4C1 solution. The aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:EtOAc. 100:0 to 80:20) afforded 7 as a light yellow solid (130 mg. 41%). UPLC/MS(ES+): m/z 635.20 [M+H]⁺.

[0400] A mixture of aq formaldehyde (37% solution. 630 uL. 0.780 mmol) and glacial AcOH (7 uL, 0.117 mmol) in THF (500 uF) was stirred at r.t. for 15 mins. Sodium azide (7.6 mg. 0.117 mmol) and 7 (50.0 mg, 0.078 mmol) were sequentially added. After 10 mins, aq. sodium ascorbate (0.5 M solution, 32 uT. 0.016 mmol) and C11SO4 (1.2 mg. 0.008 nnnol) were added. The mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The residue was treated with a 3:1 MeOH:2N aq NaOH solution (4 111T), and the mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure, and the residue was partitioned between EtOAc and water. The layers were separated, and the organic portion was dried with Na₂SO4, filtered and concentrated under reduced pressure to afford crude 8 (34 mg), which was used in next step without further purification. UPTC/MS(ES⁺): m/z 678.25 [M+H]⁺.

[0401] A solution of 8 (34 mg) in 10:1 DCM-TFA (5 mL) was stirred at r.t. for 20 mins. The reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified

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PCT/US2014/051642 by reverse phase chromatography (waterrCHsCN, 95:5 to 0:100) to afford 197 as a white solid (5.5 mg, 13% over 2 steps). UPLC/MS(ES'): m/z 558.1 1 [M+I I]⁺.

EXAMPLE 62

Preparation of Compounds 198 and 199

[0402] Potassium carbonate (40.0 mg. 0.295 mmol) and Mel (20.0 mg. 0.141 mmol) were added to a solution of 8 (80.0 mg. 0.118 mmol) in CH3CN (4 mL). The mixture was stirred at r.t. for 4 h, diluted with waler and extracted with EtOAc (3x). The combined organic portions were dried with Na?SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:EtOAc, 70:30 to 0:100) afforded the two separated regioisomers 9 (21 mg, 25%) and 10 (24 mg, 29%). 9: UPLC/MS(ES+): m/z 692.29 [M+H]⁺. 10: UPLC/MS(ES+): m/z 692.28 [M+H]\ [0403] General procedure for PMB-removal: A solution of PMB-cther (0.1 mmol) in 10:1 DCM:TFA (3 mL) w'as stirred at r.t. for 30 mins. The reaction was quenched with 2M aq. NaOH solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0 to 90:10) afforded the product. 198. (derived from 9) UPLC/MS(ES⁺): m/z 572.38 [M+H]⁺. 199: (derived from 10) UPLC/MS(ES⁺): m/z 572.43 [M+H]⁺.

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EXAMPLE 63

Preparation of Compounds 200, 201, 202, 203 and 204

[0404] Sodium hydride (1.80 g, 44.7 mmol) was added to a stirred solution of 2-1 (11.6 g. 40.7 mmol) in dry DMF (75 mL), which had been pre-cooled to 0° C. The mixture was stirred at 0° C for 10 mins, and then warmed to r.t. The mixture was then stirred for 30 mins. The reaction was cooled to 0° C and 3-bromo-2-methylprop-l-ene (5.70 g. 42.7 mmol) was added dropwise. The mixture was allowed to gradually reach r.t., and stirring was continued for 20 h. EtOAc and sat. aq. NH4CI solution were added. The layers were separated, and the organic portion was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 2-2 (12.1 g, 87%). UPLC/MS(ES⁺): m/z 339.80 [M+H]⁺.

[0405] A mixture of 2-2 (12.0 g, 35.4 mmol), sodium formate (2.70 g. 40.7 mmol), tetrabutylammonium chloride (9.80 g. 35.4 mmol), Pd(OAc)2 (396 mg . 1.7 mmol) and TEA (14.7 111L. 106 mmol) in dry⁷ DMF (300 mL) was degassed and heated to 100 °C for 3 h. EtOAc and sat. aq. NH4CI solution were added. The layers were separated, and the organic portion was washed with brine, dried with Na2SO4. filtered and concentrated under reduced pressure. Chromatography⁷ of the residue (cyclohexane.'EtOAc, 100:0 to 50:50) afforded 2-3 as a pale yellow wax (6.15 g. 81%). UPLC/MS(ES⁺): 111/z 213.91 [M+H]⁺.

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PCT/US2014/051642 [0406] A mixture of 2-3 (1.80 g, 8.45 mmol). (3-chloro-4-fluorophenyl)boronic acid (2.94 g, 16.9 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) (618 mg, 0.84 mmol) and aq. Na^CCf (2M solution, 8.45 mL. 16.9 mmol) in DCE (80 mL) was degassed and heated to 100 °C under microwave irradiation. Water and DCM were added. The layers were separated, and the organic phase was dried with l^SCfi, fdtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 2-4 as a white solid (1.97 g, 76%). UPLC/MS(ES⁺): m/z 307.18 [M+H]⁺.

[0407] Dess-Martin periodinane (6.8 g, 16.0 mmol ) was added to a stirred solution of 2-4 (1.97 g, 6.40 mmol) in dry DCM (28 mL). The mixture was stirred at r.t. under N2 atmosphere for 1 h. The reaction was quenched with a 1:1 2M aq. Na2S20a:sat. aq. NaHCOj solution (30 mL). the mixture was vigorously stirred for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cvclohexane:EtOAc 100:0 to 70:30) afforded 2-5 as a white solid (1.40 g. 72%). UPLC7MS(ES⁺): m/z 306.15 [M+H]⁺.

[0408] TMSCF3 (810 uL, 5.50 mmol) was added to a solution of 2-5 (1.40 g, 4.60 mmol) in dry DCM (25 mL). The mixture was cooled 0 °C and TBAF (IM sol in TIIF. 5.5 mL, 5.50 mmol) was added dropwise. The mixture was allowed to gradually reach r.t. and stirring was continued for 1 h. Water and DCM were added. The layers were separated, and the organic portion was dried with ixfeSCfi and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 80:20) afforded 2-6 (1.43 g, 82%). UPLC/MS(ES⁺): m/z 376.16 [M+H]⁺.

[0409] Dess-Martin periodinane (3.25 g, 7.68 mmol) was added to a stirred solution of 2-6 (1.43 g. 3.84 mmol) in dry DCM (17 mL). The mixture was stirred at r.t. for 1 h. A 1:1 2M aq. Na2S2C>3:sat. aq. NaHCOa solution was added. The mixture was stirred at r.t. for 30 mins. The layers were separated, and the aqueous portion was extracted with DCM (2x). The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 70:30) afforded 2-7 as a white solid (1.20 g. 84%). UPLC/MS(ES⁺): m/z 392.16 [M+HjO]*

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PCT/US2014/051642 [0410] Trimethylsulfoxonium iodide (695 mg, 3.16 mmol) was added to a solution of potassium tert-butoxide (354 mg, 3.16 mmol) in DMSO (6 mL). The mixture was stirred at r.t. for 30 mins. A solution of 2-7 (1.18 g, 3.16 mmol) in DMSO (20 mL) was added, and the mixture was stirred at r.t. for 30 mins. EtOAc and water were added, and the layers were separated. The aqueous portion was extracted with EtOAc. The combined organic extracts were washed with brine, dried with Na2SO4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 70:30) afforded 2-8 as a colourless wax (530 mg, 43%). UPLC/MS(ES^T): m/z 388.18 [M+H]⁺.

[0411] A solution of 2-8 (530 mg. 1.37 mmol) in 7M NPf-MeOH (50 mL) was stirred at 45 °C for 1 h. The volatiles were removed under reduced pressure. The crude was purified by reverse phase chromatography (water;CH₃CN 95:5 to 0:100) to afford 2-9 as a white solid (498 mg. 90%). UPLC/MS(ES⁺): m/z 405.21 [M+H]⁺.

|0412] Racemate 2-9 was resolved by using a prep-HPTC separation [Chiralpak AD-H (25 x 3 cm, 5 um), mobile phase: n-Hexane/(EtOH/MeOH+0.1% ipa) 96/4 % v/v, flow⁷rate: 32 niL/min, UV detection DAD 220 nm] to obtain the two separated enantiomers 2-9a (t|<=10.9 min) and 2-9b (t|<=14.5 min). UPLC and 'll NMR analyses for the two enantiomers were superimposible.

[0413] General amide coupling conditions-Method A: A mixture of 2-9 (50.0 mg, 0.124 mmol), EDC (31.0 mg, 0.161 mmol), HOBT (22.0 mg, 0.161 mmol) and acid (0.124 mmol) in DCM:DMF (5:1. 6 mL) was stirred at 45 °C for 2 h. DCM was added. The organic portion was washed with sat. aq. NH4CI solution and brine, dried with Na^SCfi. filtered and concentrated under reduced pressure. Chromatography of the residue afforded the product.

[0414] General amide coupling conditions-Method B: DIPEA (281 uL, 1.62 mmol) was added to a solution of acid (1.06 mmol) and HATU (461 mg, 1.21 mmol) in dry DMF (5 mL). After 20 mins, a solution of 2-9 (330 mg. 0.81 mmol) in DMF (5 mL) was added. The mixture was stirred at r.t. until complete. EtOAc and sat. aq. NH4CI solution were added. The layers were separated, and the aqueous portion was extracted with EtOAc.

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The combined organic portions were dried with Na₂SO4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue afforded the product.

[0415] Coupling of 2-9 with acid 2-10 according to Method A afforded 200 as a white solid (30%. mixture of 4 isomers). UPLC/MS(ES+): m/z 638.18 [M+H]⁺. Racemate 200 was resolved by using a prep-HPLC separation [Chiralpak AD-H (25 x 2 cm. 5 um). mobile phase: Ethanol+0.1% isopropylamine 20% v/v. flow rate: 45 mL/min. UV detection DAD 220 nm] to obtain the four separated isomers 201 (t_R=12.9 min), 203 (t_R=14.8 min). 202 (t_R=16.6 min) and 204 (t_R=23.6 min).

[0416] Alternatively, 2-9a and 2-9b were separately coupled with 2-10 according to Method B. Each diastereomeric mixture was resolved by chiral HPLC. 2-9a provided a mixture of 204 (t_R=6.5 min) and 202 (t_R=14.1 min) [Whelk 01 (R,R) (25 x 2.0 cm), 5 μ. mobile phase: n-Hexanc/(Ethanol+0.1% isopropylamine) 30/70 % v/v. flow rate: 17 mL/min. UV detection DAD 220 nm]. 2-9b provided a mixture of 201 and 203 (t_R 6.4 min and 12.3 min) [Whelk 01 (R.R) (25 x 2.0 cm), 5 μ, mobile phase: n-Hexane/(Ethanol+0.1% isopropylamine) 30/70 % v/v. flow rate: 17 mL/min, UV detection DAD 220 nm],

EXAMPLE 64

Preparation of 2-10

OMe

[0417] Compound 2-12 (4.86 g, 26.7 mmol) was added to a stirring suspension of cesium carbonate (15.4 g, 47.5 mmol) in DCM (120 mL). A solution of 2-11 (3.13 g. 19.0 mmol) in DCM (20 mL) was added. The mixture was stirred at r.t. for 5 h. The mixturew was filtered through a pad of Celite. washed thoroughly with DCM and concentrated. The residue was dissolved in EtOAc. The organic portion was washed with water and brine, dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 100:0 to 0:100) afforded 2-13 as a white solid (4.50 g. 89%). UPLC/MS(ES⁺): m/z 266.15 [M+H]⁺.

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PCT/US2014/051642 [0418] Lithium hydroxide monohydrate (258 mg. 6.10 mmol) was added to a suspension of 2-13 (1.50 g. 5.60 mmol) in a 1:1:6 THF:MeOH:H₂O mixture (40 mL). The mixture was stirred at r.t. for 3 h, loaded on a reverse phase cartridge and eluted with water to afford 2-10 as a white solid (1.10 g. 78%). UPLC/MS(ES⁺): m/z 252.13 [M+H]⁺.

EXAMPLE 65

Preparation of Compounds 205 and 206

[0419] Coupling of 2-9a with 3,4-dimethoxybenzoic acid according to Method A afforded 205 as a white solid (51%). UPLC/MS(ES⁺): m/z 569.40 [M+H]⁺. Using 2-9b and 3,4-dimethoxybenzoic acid according to Method A afforded 206 as a white solid (50%). UPLC/MS(ES⁺): m/z 569.40 [M+H]⁺.

EXAMPLE 66

Preparation of Compounds 207

[0420] Coupling of 2-9 with 2-14 according to Method A afforded 207 as a white solid (43%). UPLC/MS(ES⁺): m/z 576.32 [M+H]⁺.

EXAMPLE 67

Preparation of 2-14

[0421] Acrolein (21.8 mL, 326 mmol) was added to a mixture of 4-amino-3hydroxybenzoic acid (5.00 g. 33.0 mmol) in 12 N aq. HCT solution (50 mL). The mixture was refluxed for 1 h. After cooling to r.t., the mixture was concentrated under reduced

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PCT/US2014/051642 pressure. The residue was purified by reverse phase chromatography (waterrCHgCN 100:0 to 50:50) to afford 2-14 (561 mg, 9%). UPLC/MS(ES⁺): m/z 190.04 [M+I1]⁺.

EXAMPLE 68

Preparation of Compound 208

[0422] Coupling of 2-9 with 2-15 according to Method A afforded 208 as a white solid (67%). UPLC/MS(ES⁺): m/z 590.25 [M+H]⁺.

EXAMPLE 69 Preparation of 2-15

OMe OMe

2-16 O 2-15 O [0423] Cesium carbonate (2.58 g, 7.92 mmol) and Mel (822 uL, 13.2 mmol) were sequentially added to a solution of 2-14 (500 mg. 2.64 mmol) in DMF (30 mL). The mixture was stirred at r.t. for 18 h. EtOAc was added. The organic portion was washed with 2M aq. HC1 solution and water, dried with Na2SO4, filtered and concentrated under reduced pressure. Crude 2-16 was dissolved in a 2:1:1 THF:MeOH:H?O mixture (8 mL). Lithium hydroxide monohydrate (332 mg, 7.92 mmol) was added, and the mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in water, and the pH of the solution was adjusted to 6 with IM aq. HC1 solution. The aqueous portion was extracted with DCM (2x). The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-15 (227 mg), which was used in the next step without further purification. UPLC/MS(ES⁺): m/z 204.10 [M+H]⁺.

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EXAMPLE 70

Preparation of Compound 209

[0424] Coupling of 2-9 with 4-cyclopropoxy-3-methoxybenzoic acid according to Method A afforded 209 as a white solid (41%). UPLC/MS(ES⁺): m/z 595.30 [M+f11 .

EXAMPLE 71

Preparation of Compound 210

[0425] Coupling of 2-9 with 4-(carbamoylmethoxy)-3-methoxybcnzoic acid according to Method B afforded 210 as a white solid (51%). UPLC/MS(ES⁺): m/z: 612.21 [M+H]⁺.

EXAMPLE 72

Preparation of Compound 211

OH O

[0426] Coupling of 2-9 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method B afforded 211 as a white solid (45%). UPLC/MS(ES⁺): m/z 613.27 [M+H]⁺.

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EXAMPLE 73

Preparation of Compound 212

[0427] Coupling of 2-9 with 2-17 according to Method B afforded 212 as a white solid (33%). UPLC/MS(ES⁺): m/z 636.00 [M+H]⁺.

EXAMPLE 74

Preparation of 2-17

[0428] LDA (2M solution in THF. 1.05 mL. 2.10 mmol) was added to a stirred solution of l-(tert-butoxycarbonyl)-2-pyrrolidinone (276 uL, 1.62 mmol) in THF (1 mL). which had been pre-cooled to -78 °C. After 15 mins, a solution of methyl 4-(bromomethyl)3-methoxybenzoate (460 mg, 1.78 mmol) in THF (1 mL) was added drop wise to the mixture and stirring at 78 °C was continued for 1 h. The reaction was quenched with water. The aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with hboSOi. filtered and concentrated under reduced pressure. Chromatography of the residue (cvclohexane:EtOAc 70:30) afforded 2-18 (199 mg, 34%). UPLC/MS(ES⁺): m/z 364.20 [M+H]⁺.

[0429] A solution of 2-18 (199 mg, 0.547 mmol) in 5:1 DCM:TFA (3 mL) was stirred at r.t. for 5 mins. The mixture was diluted with DCM. The organic portion was washed with a sat. aq. NaHCOj solution, dried with Na/SOj, filtered and concentrated under

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PCT/US2014/051642 reduced pressure. The residue was purified by reverse phase chromatography (0.1% IICOOII:water:0.1% IICOOII:CI1₃CN 100:0 to 0:100) to afford 2-19.

[0430] Compound 2-19 was dissolved in a 2:1:1 THF:MeOH:H2O mixture (10 mL). Lithium hydroxide monohydrate (45 mg, 1.10 mmol) was added. The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford crude 217. which was directly used in the next step without further purification. UPLC/MS(ES⁺): m/z 250.20 [M+H]⁺.

EXAMPLE 75

Preparation of Compound 213

[0431] Coupling of 2-9 with 2-20 according to Method B afforded 213 as a white solid (73%). UPLC/MS(ES⁺): m/z 604.00 [M+H]⁺.

EXAMPLE 76

Preparation of 2-20

[0432] Crotonaldehyde (4.01 g. 48.9 mmol) was added dropwise to a mixture of 4-amino-3-hydroxybenzoic acid (5.00 g. 33.1 mmol) and 6M aq. HC1 solution (60 mL. 360 mmol). The mixture was refluxed for 18 h. After cooling to r.t. a precipitate formed. The solid was filtered off, dried and collected. Acid 2-21 (3.44 g) was used in the next step without further purification. UPLC/MS(FS⁺): m/z 204.10 [M+H]⁺.

[0433] Cesium carbonate (15.8 g, 48.6 mmol) and Mel (5.88 mL, 94.5 mmol) were sequentially added to a solution of 2-21 (3.04 g) in DMF (80 mL). The mixture was stirred at r.t. for 12 h. DMF was removed under reduced pressure, and the residue was taken up with EtOAc. The organic portion was washed with water, dried with NtbSOi. filtered and

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PCT/US2014/051642 concentrated under reduced pressure to afford crude 2-22 (2.76 g), which was used in the next step without further purification. UPLC/MS(ES¹): m/z 232.10 [M+I I]⁺.

[0434] Lithium hydroxide monohydrate (0.272 g, 6.49 mmol) was added to a stirred suspension of 2-22 (500 mg. 2.16 mmol) in a 2:1:2 TEELMeOEhHiO mixture. The mixture was stirred at r.t. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (wateriCHsCN 100:0 to 0:100) to afford 2-20 (291 mg). UPLC/MS(ES⁺): m/z 218.10 [M+H]⁺.

EXAMPLE 77

Preparation of Compound 214

solid (49%). UPLC/MS(ES⁺): m/z 633.26 [M+H]⁺.

EXAMPLE 78

Preparation of 2-23

Ester 2-22 (1.50 g. 6.48 mmol) was added to a suspension of selenium dioxide (1.44 g, 13.0 mmol) in pyridine (24 mL). The mixture was refluxed for 3 h. The volatiles were removed under reduced pressure, and the residue was triturated with EtOAc. The solid was dried and collected to provide 2-24 (595 mg, 35%). UPLC/MS(ES⁺): m/z 262.10 [M+H]⁺.

[0437] Oxalyl chloride (100 uL, 1.14 mmol) and DMF (1 drop) were added to a solution of 2-24 (230 mg, 0.880 mmol) in DCM (7 mL). The mixture was stirred at r.t. for 30 mins. HMDS (400 uL, 1.89 mmol) and then MeOH were added. The mixture was concentrated under reduced pressure. Chromatography of the residue (EtOAc-DCM. 100:0 to 0:100) afforded 2-25. UPLC/MS(ES⁺): m/z 261.10 [M+H]⁺.

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PCT/US2014/051642 [0438] Lithium hydroxide monohydrate (44.0 mg, 1.05 mmol) was added to a stirred suspension of 2-25 (91.0 mg, 0.350 mmol) in a 2:1:2 THF:MeOH:fl2O mixture. The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (waterCHaCN 100:0 to 0:100) to afford 2-23 (76 mg, 89%). UPLC/MS(ES⁺): m/z 247.20 [M+H]⁺.

EXAMPLE 79

Preparation of Compound 215

[0439] Coupling of 2-9 with 2-26 according to Method B afforded 215 as a white solid (41%). UPLC/MS(ES⁺): m/z 615.26 [M+H]⁺.

EXAMPLE 80 Preparation of 2-26

[0440] SOCh (420 uL, 5.76 mmol) and TEA (800 uL, 5.76 mmol) were added to a solution of 2-25 (150 mg, 0.576 mmol) in DCE (10 mL), which had been pre-cooled to 0 °C. The mixture was stirred at 0 °C for 3 h. The reaction was quenched with a sat. aq. NaHCOs solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by-⁷ reverse phase chromatography-⁷(water:CH₃CN 100:0 to 0:100) to afford 2-27 (100 mg, 71%). LJPLC/MS(ES⁺): m/z 243.18 [M+H]⁺.

[0441] Lithium hydroxide monohydrate (21.0 mg, 0.49 mmol) was added to a stirred suspension of 2-27 (100 mg, 0.413 mmol) in a 2:2:1 TLHCMeOLLELO mixture (10 111L). The mixture was stirred at r.t. for 2 h. The volatiles were removed under reduced

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PCT/US2014/051642 pressure. Crude 2-26 was used in the next step without further purification. UPLC/MS(ES⁺): m/z 229.14 [M+II]⁺.

EXAMPLE 81

! 216 [0442] Coupling of 2-9 with 2-28 according to Method B afforded 216 as a white solid (46%). UPLC/MS(ES⁺): m/z 637.30 [M+H]⁺.

EXAMPLE 82

Preparation of 2-28

2-29 O 2-28 O [0443] NaH (153 mg, 3.83 mmol) was added to a solution of imidazolidin-2-one (300 mg. 3.48 mmol) in THF (3 mL), which had been pre-cooled to 0 °C. After 1 h. methyl 4-(bromomethyl)-3-methoxybenzoate (899 mg, 3.48 mmol) was added. The mixture was stirred at r.t. for 18 h, poured in to water and extracted with EtOAc (3x). The combined organic portions were dried with NibSOj. filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc;MeOH 100:0 to 80:20) afforded 2-29 as a white solid (40 mg, 4%). UPLC/MS(ES⁺): m/z 265.20 [M+H]⁺.

|0444] Lithium hydroxide monohydrate (19.0 mg, 0.454 mmol) was added to a stirred suspension of 2-29 (40.0 mg. 0.151 mmol) in a 2:2:1 THF:MeOH:H2O mixture (8 mL). The mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure. The residue was taken up with water, and the aqueous portion was extracted with EtOAc (2x). The combined organic portions were dried with Na?SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc.MeOH 100:0 to 80:20) afforded 2-28 as a white solid (32 mg, 84%). LPLC/MS(ES'): m/z 251.20 [M+H]⁺.

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EXAMPLE 83

Preparation of Compound 217

methoxy-4-[(2-oxopyrrolidin-3-yl)oxy]benzoic acid (130 mg, 0.517 mmol). HOBT (87.3 mg. 0.646 mmol). EDC (124 mg, 0.646 mmol) and 2-30 (104 mg, 0.431 mmol) in a 4:1 DCM:DMF (5 mL). The mixture was warmed to 45 °C and stirred at 45 °C for 18 h. A IM aq. HC1 solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with IM aq. HC1 solution, dried with NibSOi. filtered and concentrated under reduced pressure to afford crude 2-31 (203 mg), which was used in the next step without further purification. UPLC/MS(ES⁺): m/z 476.30 [M+I I] .

[0446] Dess-Martin periodinanc (453 mg, 1.07 mmol ) was added to a stirred solution of 2-31 (203 mg) in dry DCM (10 mL). The mixture was stirred at r.t. for 2 h. and the reaction was quenched with a 1:1 IM aq. Na2S2O3:sat. aq. NaHCOs solution (3 mL). The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with MoStf. filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0 to 75:25) afforded 2-32 (80 mg, 39% over two steps). UPLC/MS(ES⁺): m/z 474.30 [M+H]⁺.

[0447] A mixture of 2-32 (10.0 mg, 0.021 mmol), (3-chloro-4fluorophenyl)boronic acid (18.4 mg, 0.105 mmol), Pd(dppf)C12 (2.0 mg, 0.003 mmol) and aq. Na2COj (2M solution. 0.105 mmol, 0.05 mL) in DCE (0.3 mL) was degassed and stirred while heated to 85 °C under microwave irradiation (4 cycles for 10 mins each). After each run. a further aliquot of Pd(dppf)Cb (2.0 mg, 0.003 mmol) was added. The reaction was

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PCT/US2014/051642 diluted with water, and DCM were added. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (waterCHaCN 100:0 to 0:100) to afford 217. UPLC/MS(ES⁺): m/z 568.30 [M+H]⁺.

EXAMPLE 84

Preparation of Compound 218

[0448] Trimethylsulfoxonium iodide (21.0 mg, 0.097 mmol) was added to a solution of potassium tert-butoxide (9.8 mg, 0.086 mmol) in DMSO (0.6 mL). The mixture was stirred at r.t. for 30 mins. A solution of 218-1 (50.0 mg, 0.088 mmol) in DMSO (0.6 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na₂SO|. filtered and concentrated under reduced pressure to afford crude 2-33 (50 mg), which was used next step without further purification. UPLC/MS(ES⁺): m/z 582.34 [M+H]⁺.

[0449] A mixture of 2-33 (50 mg), potassium carbonate (24.0 mg. 0.170 mmol) and pyrazole (24.0 mg, 0.350 mmol) in DMF (1 mL) was stirred at 40 °C for 18 h. The mixture was diluted with EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (waterC'ffCN 100:0 to 50:50) to afford 218 as a white solid (10 mg. 17% over two steps). UPLC/MS(ES⁺): m/z 650.40 [M+H]⁺.

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EXAMPLE 85

Preparation of Compound 219

[0450] Epoxide 2-33 (60 mg. crude) was dissolved in a 1:1 3M aq. HC1 sol:MeOH mixture (5 mL). The mixture was heated to 50 °C for 3 h. After cooling to r.t., the mixture was basified with IM aq. NaOH solution and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (waterCHaCN 95:5 to 0:100) to afford 219 as a white solid (18 mg. 26% over two steps). UPLC/MS(ES⁺): m/z 600.36 [M+H]⁺.

EXAMPLE 86

Preparation of Compound 220

OMe

[0451] Triethylamine (0.35 mL. 2.51 mmol) was added to a mixture of 8methoxyquinoline-6-carboxylic acid (286 mg, 1.18 mmol). HOBT (223 mg, 1.65 mmol), EDC (316 mg. 1.65 mmol) and 2-30 (239 mg, 1.18 mmol) in DCM (7 mL). The mixture was stirred at r.t. for 60 h. AIM aq. HCI solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with IM aq. HCI solution, dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-34, which was used in the next step without further purification. UPLC/MS(ES⁺): m/z 428.30 [M+H]⁺.

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PCT/US2014/051642 [0452] Dess-Martin periodinane (1.20 g. 2.82 mmol ) was added to a stirred solution of 2-34 in dry DCM (6 mL). The mixture was stirred at r.t. for 2 h, and the reaction quenched with a 1:1 IM aq. Na₂S₂O₃:sat. aq. NaHCO₃ solution. The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na₂SO₄. filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 80:20 to 0:100) to afford 2-35 (11.0 mg, 2% overall). UPLC/MS(ES⁺): m/z 426.20 [M+H]⁺.

[0453] A mixture of 2-35 (11.0 mg, 0.026 mmol), (3-chloro-4fluorophenyl)boronic acid (11.2 mg. 0.065 mmol), Pd(dppf)Cl₂ (1.3 mg. 0.002 mmol) and aq. Na₂CO₃ (2M solution, 39 uL, 0.078 mmol) in DCE (1 mL) was degassed and heated to 85 °C for 24 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 30:70) to afford 220 as an off-white solid (2.3 mg, 17%). UPLC/MS(ES⁺): m/z 520.30 [M+H]⁺.

EXAMPLE 87

Preparation of Compound 221

[0454] Trimethylsulfoxonium iodide (18.3 mg. 0.087 mmol) was added to a solution of potassium tert-butoxide (9.3 mg. 0.083 mmol) in DMSO (0.3 mL). The mixture was stirred at r.t. lor 30 mins. A solution of 220 (43.0 mg. 0.083 mmol) in DMSO (0.7 mL) was added, and the mixture was stirred at r.t. for a further 30 mins. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na₂SO₄. filtered and concentrated under reduced pressure. The residue was dissolved in a 1:1 3M aq. HC1 sokMeOEI mixture (3 mL). and the mixture was heated to 50 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford 221 as an off-white solid. UPLC/MS(ES⁺): m/z 552.38 [M+H]⁺.

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EXAMPLE 88

Preparation of Compound 222

[0455] NaH (59.0 mg, 1.47 mmol) was added to a solution of 2-13 (300 mg, 1.13 mmol) in dry THF (4.5 mL). After 5 mins of stirring at r.t., Mel (192 mg, 1.35 mmol) was added. The reaction was stirred at r.t. for 3 h. EtOAc and IM aq. HCl solution were added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₃SO₄ and filtered. The volatiles were removed under reduced pressure to afford crude 2-36, which was in the next step without further purification. Lithium hydroxide monohydrate (95.0 mg, 2.26 mmol) was added to a stirred mixture of 2-36 in 2:1:1 THF:MeOH:H2O (8 mL). The reaction was stirred at r.t. for 3 h. Additional lithium hydroxide monohydrate (95 mg) was added and stirring was continued for 2 h. The mixture was poured in to 6M aq. HCl solution. The aqueous portion was saturated with NaCl and extracted with EtOAc and DCM. The combined organic portions were dried with Na₃SO4, and filtered. The volatiles were removed under reduced pressure to afford crude 2-37. which was in the next step without further purification. UPLC/MS(ES⁺): m/z 266.20 [M+H]⁺.

[0456] A mixture of 2-37, 2-30 (273 mg, 1.13 mmol). EDC (282 mg. 1.47 mmol), HOBT (198 mg. 1.47 mmol) and TEA (267 uL. 1.92 mmol) in DMF (8 mL) was stirred at r.t. for 18 h. EtOAc and 2M aq. HCl solution were added. The layers were separated, and the organic portion was concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CI I₃CN 100:0 to 0:100) to afford 2-38 as a colorless wax (90 mg. 16% over 3 steps). UPLC/MS(ES⁺): m/z 490.30 [M+H]⁺.

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PCT/US2014/051642 [0457] Dess-Martin periodinane (195 mg, 0.46 mmol) was added to a stirred solution of 2-38 (90.0 mg, 0.184 mmol) in dry DCM (2 mL). The mixture was stirred at r.t. for 2 h. The reaction was quenched with a 1:1 IM aq. Na^SoCtysat. aq. NaHCCL solution. The mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-39 (92 mg), which was in the next step without further purification. UPLC/MS(ES⁺): m/z 488.30 [M+H]⁺.

[0458] A mixture of 2-39 (92 mg). (3-chloro-4-fluorophenyl)boronic acid (83.0 mg, 0.475 mmol). Pd(dppf)CL (27.6 mg. 0.038 mmol) and aq. Na2CO₃ (2M solution, 285 uL. 0.570 mmol) in DCE (3 mL) was degassed and heated to 100 °C under microwaive irradiation for 1.5 h. Water and DCM were added. The layers were separated, and the organic portion was dried wtih Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (w^Tater:CH₃CN 100:0 to 0:100) to afford 222 as an off-white solid (27.0 mg. 25% over two steps). UPLC/MS(ES⁺): m/z 582.30 [M+H]⁺.

EXAMPLE 89

Preparation of Compound 223

to a solution of 2-5 (1.03 g, 3.37 mmol) in tert-butanol (60 mL). A solution of sodium chlorite (609 mg, 6.74 mmol) and sodium phosphate monobasic dihydratc (3.41 g, 21.9 mmol) in water (60 mL) was then added. The mixture was stirred at r.t. for 18 h. Brine was added, and the aqueous portion was extracted with EtOAc (3x). The combined organic portions were were dried with Na2SO₄, filtered and concentrated under reduced pressure.

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Chromatography of the residue (cyclohexane:EtOAc 100:0 to 0:100) afforded 2-40 as an offwhite solid (688 mg, 63%). LIPLC/MS(ES^H): m/z 322.10 [M+I I]⁺.

[0460] Triethvlamine (0.160 mL, 1.12 mmol) was added to a mixture of 2-40 (200 mg, 0.622 mmol), HOBT (151 mg. 1.12 mmol). EDC (167 g. 0.870 mmol) and N.Odimethylhydroxylamine hydrochloride (91.1 mg. 0.934 mmol) in DCM (15 mL). The mixture was stirred at r.t. for 18 h. AIM aq. HC1 solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with IM aq. HC1 solution, dried with Na₃SO4. filtered and concentrated under reduced pressure to afford crude 2-41 (255 mg) which was used in the next step without further purification. UPLC/MS(ES⁺): m/z found 365.20 [M+H]⁺.

[0461] Cyclopropylmagnesium bromide (IM solution in 2-methyl tetrahydro furan, 1.96 mL, 1.96 mmol) was added to a solution of 2-41 (255 mg) in THF (10 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. aq. NH4CI solution and extracted with DCM (3x). The combined organic portions were dried with NibSO i. filtered and concentrated under reduced pressure. Chromatography of the residue (cvclohexane-EtOAc. 100:0 to 50:50) afforded 2-42 (146 mg, 68% over 2 steps). UPLC/MS(ES⁺): m/z: 346.20 [M+H]⁺.

[0462] A mixture of trimethylsulfoxonium iodide (93.0 mg, 0.423 mmol) and NaH (16.9 mg, 0.423 mmol) in 1:1 DMSO:THF (1 mL) was stirred at r.t. for 1 h. A solution of 2-42 (146 mg, 0.423 mmol) in THF (1 mL) was added, and the mixture was stirred at r.t. for 18 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-43 (180 mg), which was used in the next step without further purification.

[0463] A solution of 2-43 (180 mg) in 7M NH₃:MeOH (4 mL) was stirred at r.t. for 18 h and at 35 °C for an addition 24 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-44 (13 mg, 8% over 2 steps). UPLC/MS(ES⁺): m/z 377.20 [M+H]⁺.

[0464] A mixture of 2-10 (39.9 mg 0.159 mmol). HOBT (25.8 mg, 0.191 mmol). EDC (28.4 mg. 0.148 mmol), TEA (0.027mL, 0.191 mmol) and 2-44 (40.0 mg, 0.106 mmol)

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PCT/US2014/051642 in DMF (2 mL) was stirred at r.t. for 18 h. AIM aq. HC1 solution was added, and the mixture was stirred at r.t. for 10 mins. The layers were separated. The organic portion was washed with IM aq. HCI solution, dried with Na?SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN

100:0 to 0:100) to afford 223 (8 mg, 12%). UPTC/MS(ES⁺): m/z 610.50 [M+H]⁺.

EXAMPLE 90

Preparation of Compound 224

[0465] Coupling of 2-44 with 2-14 using conditions reported for the preparation of 223 (EDC, HOBT) afforded 224 as a white solid. UPLC/MS(ES⁺): m/z 562.40 [M+H]⁺.

EXAMPLE 91

Preparation of Compound 225

[0466] Trimethylsulfoxonium iodide (21.5 mg, 0.098 mmol) was added to a mixture of potassium tert-butoxide (9.98 mg. 0.089 mmol) in DMSO (2 mL). After 30 mins. 2-45 (57.8 mg, 0.089 mmol) was added, and the mixture was stirred at r.t. for 1.5 h. The mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO|. filtered and concentrated under reduced pressure to afford crude 2-46, which was used in the next step without purification. Crude 2-46 was dissolved in DMF (1 mF). K2CO3

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PCT/US2014/051642 (24.6 mg, 0.178 mmol) and imidazole (12.1 mg, 0,178 mmol) were then sequentially added.

The mixture was heated to 80 °C and stirred at 80 °C for 48 h. The volatiles were removed under reduced pressure to afford crude 2-47, which was used in the next step without purification.

[0467] A solution of 2-47 in 1:1 TFA:DCM (0.9 mL) was stirred at r.t. for 1 h. The reaction was quenched with a IM aq. NaOH solution. After 30 mins of stirring at r.t.. the layers were separated. The organic portion was dried with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to afford 225 as a white solid (1 mg, 2% overall). UPLC/MS(ES⁺): m/z 611.30 [M+H]⁺.

EXAMPLE 92

Preparation of Compound 226

trimethylsulfoxonium iodide (49.7 mg, 0.226 mmol) in DMSO (2 mL). After 40 mins a solution of 220 (117 mg. 0.226 mmol) in THF (2 mL) was added, and the mixture was stirred at r.t. for 6 h. The mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure to afford crude 2-48. which was used in the next step without purification. UPLC/MS(ES⁺): m/z 534.30 [M+H]⁺.

[0469] Potassium carbonate (31.3 mg, 0.452 mmol) and imidazole (30.8 mg, 0.452 mmol) were sequentially added to a solution of 2-48 in DMF (2 mL). The mixture was heated to 120 °C for 18 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (watenCHsCN 100:0 to 0:100) to afford 226 as a white solid (10 mg, 7% over 2 steps). UPLC/MS(ES⁺): m/z 602.50 [M+H]⁺.

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EXAMPLE 93

Preparation of Compound 227

[0470] A mixture of 2-49 (110 mg, 0.0 mmol), HOBT (86.0 mg, 0.640 mmol). F.DC (122 mg. 0.640 mmol), TEA (120 uL. 0.860 mmol) and 4-(2-fluoroethoxy)-3methoxybenzoic acid (110 mg, 0.510 mmol) in DCM (4 mL) was stirred at r.t. for 3 h. The reaction was quenched with IM aq. HC1 solution, and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the organic portion was washed with IM aq. HC1 solution, dried with Na^SOi. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc 60:40 to 10:90) afforded 2-50 as a white solid (95 mg, 48%). UPLC/MS(ES⁺): m/z 453.09 [M+H]⁺.

[0471] A mixture of 2-50 (45.0 mg, 0.100 mmol), (3-chloro-4fluorophenyl)boronic acid (87.0 mg, 0.500 mmol), Pd(dppf)Cl₂ (3.6 mg, 0.005 mmol) and aq. NajCOs (2M solution, 250 uL, 0.500 mmol) in DCE (1 mL) was degassed and stirred with heating to 85 °C for 3 h. Water and DCM were added. The layers were separated, and the organic phase was dried with Na^SCfi, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (waterCFfiCN 100:0 to 50:50) to afford 227 (10.5 mg. 19%). UPLC/MS(ES⁺): m/z 547.30 [M+H]⁺.

EXAMPLE 94

Preparation of Compound 228

|0472] A mixture of 2-50 (50.0 mg. 0.110 mmol). 7-fluoro-3-(tetramethyl-l,3.2dioxaborolan-2-yl)-l-{[2-(trimethylsilyT)ethoxy]methyl}-lH-indole (108 mg, 0.270 mmol),

Pd(dppf)Cl₂ (4.0 mg, 0.005 mmol) and aq. Na₂CC>3 (2M solution, 135 uL, 0.270 mmol) in

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DCE (1 mL) was degassed and stirred with heating to 85 °C for 5 h. Water and DCM were added, and the layers were separated. The organic phase was dried with NaiSCfi, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-51.

[0473] A solution of 2-51 in 10:1 DCM:TFA (1.1 mL) was stirred at r.t. for 3 h. A IM aq. NaOH solution was added, and the mixture was stirred at r.t. for 18 h. The layers were separated, and the organic phase was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 50:50) to afford 228 (4.2 mg, 7% over 2 steps). UPLC/MS(ES⁺): m/z 552.40 [M+H]⁺.

EXAMPLE 95

Preparation of Compound 229

[0474] A mixture of 4-amino-3-hydroxybenzoic acid (2.01 g. 13.1 mmol). 12M aq. HCI solution (20mL. 240 mmol) and 3-buten-2-one (1.59 mL, 19.6 mmol) was refluxed for 4 h. The volatiles were removed under reduced pressure, and the residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford 8-hydroxy-4metliylquinoline-6-carboxylic acid (830 mg. 31%). This was dissolved in DMF (35 mL). Cesium carbonate (4.42 g, 13.6 mmol) and iodomethane (1.28 mL, 20.5 mmol) were sequentially added to the solution. The mixture was stirred at r.t. for 4 h. The volatiles were removed under reduced pressure, and the residue was taken up with EtOAc. The organic portion was washed with water, dried with \la2SO4. filtered and concentrated under reduced pressure to afford crude 2-52 (860 mg), which was used in the next step without further purification. UPLC/MS(ES⁺): m/z 232.10 [M+H]⁺.

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PCT/US2014/051642 [0475] Lithium hydroxide monohydrate (280 mg, 6.73 mmol) was added to a stirred suspension of 2-52 (220 mg) in a 2:1:1 TI IFAdeOfEEfO mixture (4 mL). The mixture was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was dissolved in water, and the pH of the aqueous portion was adjusted to 6 with IM aq. HC1 solution. The mixture was purified by reverse phase chromatography (water:CH₃CN 100:0 to 0:100) to afford 2-53 (80 mg, 31%). UPLC/MS(ES⁺): m/z 218.10 [M+H]⁺.

[0476] Coupling of 2-53 with 2-30 according to Method A afforded 2-54, which was used in the next step without further purification.

[0477] Dess-Martin periodinane (127 mg. 0.299 mmol) was added to a stirred solution of 2-54 (66 mg) in dry DCM (32 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with a 1:1 IM aq. Na2S2C>3:sat. aq. NaHCO₃ solution, and the mixture was stirred vigorously for 30 mins. The layers were separated, and the organic portion was washed with brine, dried with Na2SC>4, filtered and concentrated under reduced pressure to afford crude 2-55. which was used in the next step without further purification.

[0478] A mixture of 2-55, (3-chloiO-4-fluorophenyl)boronic acid (52.0 mg. 0.299 mmol). Pd(dppf)C12 (16.0 mg. 0.022 mmol) and aq. Na2CO₃ (2M solution. 222 uL. 0.447 mmol) in DCE (31 mL) was degassed and heated to 100 °C under microwave irradiation. After 2.5 h, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN 100:0 to 50:50) to afford 229 (10.0 mg). UPLC/MS(ES'): m/z 534.30 [M+H]'.

EXAMPLE 96

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PCT/US2014/051642 [0479] Methyl magnesiumbromide (3M solution in hexane, 300 uL, 0.892 mmol) was added to a solution of 3-1 (185 mg, 0.297 mmol) in dry THF (5 mL). The mixture was stirred at r.t. for 1 h. The reaction was quenched with IM aq. HC1 solution and EtOAc was added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na^SCfi. filtered and concentrated under reduced pressure to afford crude 3-2 (201 mg), which was used in the next step without further purification.

[0480] A solution of 3-2 (201 mg) in a 10:1 DCM:TFA (3 mL) was stirred at r.t. for 40 mins. The reaction was quenched with IM aq. NaOH solution, and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the aqueous portion was extracted with DCM. The combined organic portions were dried with NinSO i and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (EtOAc:MeOH 100:0 to 80:20) afforded the two separated diastereomers (each as a racemic mixture, relative stereochemistry arbitrarily assigned). 230: while solid (10 mg, 7% overall) and UPLC/MS(ES⁺): m/z 519.30 [M+H]⁺. 231: white solid (37 mg, 24% overall) and LJPLC/MS(ES⁺): m/z 519.30 [M+H]⁺.

EXAMPLE 97

Preparation of Compound 232

232-1 232-2 232-3 232-4

[0481] To a solution of 232-1 (21.8 g, 69.9 mmol) and ethyl 2,2,2-trifluoroacetate (12.9 g. 90.8 mmol) in THF (500 mL) was added isopropyl-magnesium chloride (46.0 mL, 2.3 N in THF) at 0°C. The mixture was stirred at 0°C for 30 mins. The reaction was quenched with sat. NH4CI solution and extracted with EA. The combined organic phases were dried over anhydride MgSO , and evaporated under reduced pressure. The residue was

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PCT/US2014/051642 purified by column chromatography on silica gel (PE:EA, 5:1) to give 232-2 as an oil (16.5 g, 83.8%).

[0482] To a solution of 232-2 (16.5 g, 58.5 mmol), (3-chloro-4fluorophenyl)boronic acid (10.51 g. 58.6 mmol). KF (7.1 g, 117 mmol) in dioxane (300 mL) and FLO (30 mL) was added Pd(dppf)C12 (4.7 g, 5.8 mmol). The mixture was degassed and then charged with nitrogen (3x). The mixture was stirred at 70 °C in an oil bath for 6 h under N2. The mixture was cooled to r.t., diluted with EA and separated from the water layer. The organic phase was washed with brine, dried over anhydrous Na2SO4 and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA. 10:1) to give 232-3 as a white solid (17.0 g, 87.2%). ESI-MS: m/z 351.8 [M+H₂O]⁺.

[0483] A mixture of 232-3 (17.0 g, 51.1 mmol) and K2CO3 (13.8 g. 100 mmol) in nitro-methane (100 mL) was stirred at r.t. for 10 h. The solution was extracted with EA (3 x 200 111L). The combined organic phases were dried over anhydrous MgSO₍ and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using 15% EA in PE to give 232-4 as a white solid (16.0 g, 80.0%).

[0484] To a solution of 232-4 (16.Og, 40.6 mmol) and NiCfitoHiO (9.5 g, 40.4 mmol) in anhydrous MeOH (150 mL) and anhydrous EHF (150 mL) was added NaBH₄ (15.2 g. 400.6 mmol) in portions at 0 °C. After addition was complete, the solution was stirred at 0 °C for 1 h. The reaction was quenched with H₂O and then extracted with EA (3 x 200 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO₄. and concentrated under reduced pressure. The residue was purified by column chromatography using EA to give 232-5 as an oil (11.0 g, 74.8%). ESI-MS: m/z 365 [M+H]⁺.

[0485] To a solution of (R)-3-chloro-4-(2-hydroxypropoxy)benzoic acid (115 mg. 0.5 mmol), HATU (260 mg. 0.7 mmol) and DIPEA (320 mg. 2.5 mmol) in anhydrous DCM (5 mL) was added 232-5 (180 mg, 0.5 mmol) at 25 °C. The solution was stirred for 1 h at 25 °C. The mixture was diluted with 1.0 N aqueous Nal ICO; solution, and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO₄, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 232 as a white solid (80 mg. 27.5%). ESI-MS: m/z 576.9 [M+H]⁺.

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EXAMPLE 98

Preparation of Compound 233

[0486] To a solution of 233-1 (1.8 g, 10.0 mmol) and F3CCH2I (2 g. 10.0 mmol) in DMF (100 mL) was added K2CO3 (2.6 g, 20.0 mmol). The mixture was stirred at 80 °C for 3 h. The mixture was concentrated at low pressure, and the reidue was dissolved in EA (50 mL). The mixture was washed with brine, dried over anhydrous Na2SO₄ and concentrated to dryness. The crude product was purified by column chromatography using 10% EA in PE to give 233-2 (1.6 g, 60%).

[0487] To a solution of 233-2 (1.5 g. 5.7 mmol) in CH3OH and water (120 mL and 30 mL) was added LiOH (270 mg, 11.3 mmol). The mixture was stirred at 70 °C for 2 h. and then cooled to r.t. The mixture was extracted with EA. and the residue was neutralized using 2.0 N HC1 solution. The mixture was extracted with EA (3 x 30 mL). The organic layer was washed with brine and dried over anhydrous Na2SO4. The solution was concentrated at low pressure to give 233-3 as a white solid (1.3 g. 85%).

[0488] Compound 233 was prepared essentially as described in the preparation of 232 by using 233-3 and 232-5. Compound 233 was obtained as a white solid. (100 mg, 67%) +ESI-MS:m/z 596.1 [M+H]⁺.

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EXAMPLE 99

Preparation of Compound 234

[0489] Lo a solution of 234-1 (1.0 g, 5.4 mmol) in MeCN (10 mL) were added 1chloro-2-propanone (1.0 g, 10.0 mmol) and K2CO3 (3.5 g, 20.0 mmol). The mixture was stirred at 80 °C for 1 h. After fdtration. the filtrate was concentrated at low pressure. The residue was purified by chromatography to give 234-2 (850 mg, 65.4%).

[0490] A mixture of 234-2 (500 mg, 2.1 mmol) and DAST (5 mL) was stirred at 50 °C for 12 h. The reaction was quenched with sat. NaHCCf solution, and extracted with LA (3 x 20 mL). The organic layer was washed with brine, dried over anhydrous Na2SO4. and concentrated to dryness. Ihc residue was purified by column chromatography using 10% EA in PE to give 234-3 (310 mg, 56.8%).

[0491] Compound 234-4 was prepared essentially as described in the preparation of 233-3. Compound 234 was prepared essentially as described in the preparation of 232 by using 234-4 and 232-5. Compound 234 was obtained as white solid (58 mg. 24.1%). +ES1MS:m/z 593.1 [M+H]⁺.

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EXAMPLE 100

Preparation of Compound 235

|0492| To a solution of 235-1 (1.82 g. 10.0 mmol), tetrahydrofuran-3-ol (880 mg, 10.0 mmol) and PPI13 (2.62 g, 10.0 mmol) in THF (30 mL) at 0 °C was added D1AD (2.02 g, 10.0 mmol) dropwise. The mixture was stirred at 50 °C for 2 h, and the reaction was then quenched with sat. NaHCOs solution. The aqueous layer was extracted by DCM (3x). The combined organic layers were dried over MgSO_i, filtered and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel to give 235-2 (2.4 g, 89.6%).

[0493] Compound 235-3 was prepared essentially as described in the preparation of 233-3. Compound 235 was prepared essentially as described in the preparation of compound 232 by using 235-3 and 232-5. Compound 235 was obtained as white solid (75 mg. 62.3%). +EST-MS:m/z 585.2 [M+H]⁺.

EXAMPLE 101

Preparation of Compound 236

[0494] Compound 236 was prepared essentially as described in the preparation of compound 235 by using methyl 4-hydroxy-3-methoxybenzoate. Compound 236 was obtained as white solid (56 mg, 22.7 %). +ESl-MS:m/z 583.1 [M+I I]⁺.

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EXAMPLE 102

Preparation of Compound 237

[0495] To a solution of 237-1 (0.93 g. 5 mmol) in acetone (30 mL) was added K2CO3 (2.08 g, 15 mmol) and 2-iodoacetamide (1.39 g. 7.5 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with water and extracted with EA (4 x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuum to give crude 237-2. which was further purified by column chromatography on silica gel (PE:EA= 2:1) to 237-2 (1.01 g, 83.1%) as a white solid.

[0496] Compound 237-3 was prepared essentially as described in the preparation of 233. Compound 237 was prepared essentially as described in the preparation of 236 by using 237-3 and 232-5. Compound 237 was obtained as white solid (32 mg. 22.2%). +ES1MS:m/z 576.1 [M+H]⁺.

EXAMPLE 103

Preparation of Compounds 238, 239 and 240

0

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PCT/US2014/051642 [0497] Compound 240 was prepared essentially as described in the preparation of

232 by using 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid and 232-5. Compound 240 was obtained as a white solid (300 mg, 52.5%).

[0498] Compound 240 (3 00 mg, 0.53 mmol) was separated via SFC to give two enantiomers: 238 (140 mg, 93.3%) and 239 (100 mg, 66.7%). Compound 238: +ESTMS:m/z 572.1 [M+H]⁺. Compound 239: +ESI-MS:m/z 572.0 [M+H]⁺.

EXAMPLE 104

Preparation of Compounds 241, 242 and 243

[0499] To a solution of 243-1 (714 mg, 2.0 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 mL, 0.5 M in TI IF). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layers was washed with brine, dried over anhydrous Na₂SO4, and concentrated at low pressure. Crude 243-2 was directly used in the next step. +ESI-MS: m/z 399.0 [M+H]⁺.

[0500] Compound 243-2 (600 mg), NIL · H₂O (10 mL) and ethanol (10 mL) were put in an autoclave. After sealing, the reaction was stirred at r.t. for 10 h. The mixture was extracted by EA (3x10 mL), dried over anhydrous Na₂SO4, and concentrated at low pressure to give 243-3, which was used without further purification. +EST-MS: m/z 336.1 [M+H]⁺.

[0501] Compound 243 was prepared essentially as described in the preparation of 232 by using 4-(2-hydroxyethoxy)-3-methoxybenzoic acid and 243-3. Compound 243 was obtained as a white solid (152 mg. 23%). +ESI-MS: m/z 531.2 [M+H]⁺.

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PCT/US2014/051642 [0502] Compound 243 (152 mg, 0.28 mmol) was separated via SFC to give two isomers: 242 (40.0 mg, 26%) and 241 (43.0 mg, 26%). 241: +ES1-MS: m/z 531.1 [M+H]⁺.

242: +ESI-MS: m/z 531.1 [M+H]⁺.

EXAMPLE 105

Preparation of Compound 244

Ο O

o

[0503] Compound 244-2 was prepared as described in Franck et al., Bioorganic & Medicinal Chemistry, (2013) 21(3):643-652. Compound 244-3 was prepared essentially as described in the preparation of 235 by using 244-4 and methyl 4-hydroxy-3methoxybenzoate. Compound 244-3 was obtained as a white solid (2.8 g. 73.7%).

[0504] To a solution of 244-3 (2.8 g, 8.2 mmol) in methanol (15 mL) was added Pd(OH)2 on charcoal (10%, 500 mg) under N₂. The suspension was degassed under vacuum and purged with IL (3x). The mixture was stirred under IL (40 psi) at r.t. for 3 h. The suspension was filtered through a pad of Celite. and the pad cake was washed with methanol. The combined filtrates were concentrated to give crude 244-4 (1.7 g, 84.5%), which was used in the next step without purification.

[0505] To a solution of 244-4 (1.3 g, 5.2 mmol) in DCM (10 mL) was added DMP (3.4 g. 8.0 mmol). The mixture was stirred at r.t. for 40 mins. The reaction was quenched by sat. NaiSiO; solution and extracted with EA. The combined organic layers were washed with sat. NaHCOs solution, brine and dried over anhydrous NajSCfi. The solution was

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PCT/US2014/051642 concentrated to dryness, and the residue was purified by column chromatography on a silica gel column (PE:EA, 5:1) to give 244-5 as a white solid (0.8 g, 61.6%).

[0506] Compound 244-5 (500 mg. 2.0 mmol) was treated with DAST (5 mL), and stirred at 0 °C for 30 mins. The reaction was quenched by a sat. NaHCO₃ solution at 0 °C. and then extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA, 10:1) to give 244-6 as a white solid (605 mg. 81.2%).

I SI-MS: m/z 273.1 | Μ 111 .

[0507] To a solution of 244-6 (300 mg, 1.1 mmol) in MeOEl (35 mL) was added NaOH solution (2 N. 35 mL). The reaction was stirred under reflux for 1 h. The mixture was neutralized with 2.0 N HC1 solution, and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous MgSO4 and evaporated under reduced pressure to give 244-7 as a white solid (250 mg. 88.1%). +ES1-MS: m/z 259 [M+H]⁺.

[0508] Compound 244 was prepared essentially as described in the preparation of compound 232 by using 244-7 and 232-5. Compound 244 was obtained as a white solid (60 nig, 25.5%). +ESI-MS: m/z 606.1 [M+Hf.

EXAMPLE 106

Preparation of Compound 245

[0509] Compound 245 was prepared essentially as described in the preparation of 235. Compound 245 was obtained as a white solid (70 mg. 54.8%). +ESI-MS:m/z 569.1 [M+H]⁺.

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EXAMPLE 107

Preparation of Compound 248

248-5 248-6 ²⁴⁸-⁷

Br

[0510] Compound 248-2 was prepared as described in Rye et al., Eur. J. Med. Chem. (2013) 60:240-248. To a solution of 248-2 (6.0 g, 29.41 mmol) and K2CO3 (5.28 g. 38.23 mmol) in DMF (50 mL) was added methyl 2,4-dibromobutanoate (9.86 g. 38.23 mmol). The mixture was stirred at 80 °C for 12 h, and then diluted with water and extracted with EA (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel crude 248-3 (9.8 g).

[0511] To a solution of 248-3 (9.8 g, 25.8 mmol) in THF (100 mL) was added tBuOK (28.37 mL, 28.37 mmol, 1 N in THF) at 0 °C. The mixture was stirred at r.t. for 3 h. The mixture was diluted with water and extracted with EA (3 x 60 mL). The combined organic layer was dried over anhydrous Na2SCL and concentrated at low⁷ pressure. The residue was purified by column chromatography to give 248-4 (6.0 g. 78.0%).

[0512] To a solution of 248-4 (6.0 g, 20.0 mmol) in EtOH (20 mL) was added NaBH4 (2.10 g. 30.0 mmol) at r.t. The mixture w⁷as stirred at r.t. for 10 mins. The mixture was heated to reflux for 10 h and then cooled to r.t. The mixture was diluted with EA (60

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PCT/US2014/051642 mL) and washed with brine. The combined organic layer was dried over anhydrous Na?SO4 and concentrated at low pressure. The residue was purified by chromatography to give 248-5 (4.5 g) as a white solid.

[0513] To a solution of 248-5 (500 mg, 1.84 mmol) in DCM (10 mL) was added EtsN (370 mg, 3.68 mmol) and DMAP (10.0 mg. 0.082 mmol). TsCl (459 mg. 2.41 mmol) was added portionwise. The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic layer were dried over anhydrous Na^SCfi and concentrated at Ioav pressure. The residue was purified by column chromatography on silica gel to give 248-6 as a white solid (730 mg, 93.1%).

[0514] To a solution of 248-6 (730 mg, 1.80 mmol) in anhydrous THE (10 mL) was added TBAF (IM in THE) (5.0 mL, 5.0 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with EA (20 mL) and washed with brine. The combined organic layer was dried over anhydrous Na₂SO₍ and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 248-7 as a white solid (330 mg, 67.0%).

[0515] To a solution of 248-7 (330 mg. 1.2 mmol) in anhydrous THF (10 mL) was added /r-BuLi (0.63 mL, 1.6 mmol) at -78 °C dropwise. The mixture was stirred at -78 °C for 0.5 h. ClCOOCff (0.69 g, 7.2 mmol) was added in one portion and stirred at -78 °C for 1 h. The mixture was diluted with EA (20 mL) and washed with brine. The combined organic layer was dried over anhydrous \aKO4 and concentrated at low pressure. The residue was purified by chromatography to give 248-8 as a white solid (203 mg, 66.0%).

[0516] Compound 248-9 was prepared essentially as described in the preparation of 233. Compound 248 was prepared essentially as described in the preparation of 232 by using 248-9 and 248-10. Compound 248 was obtained as a white solid (12 mg. 3.7%). +ESI-MS:m/z 587.1 [M+H]⁺.

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EXAMPLE 108

Preparation of Compound 249

[0517] Compound 249-2 was prepared essentially as described in the preparation of 248. To a solution of 249-2 (1.02 mg. 2.5 mmol) in DMSO (10 mL) was added NaBEL (285 mg. 7.5 mmol) at r.t. under N2 atmosphere. The solution was heated to 80 °C and stirred for 1 h. The solution was cooled to r.t. The reaction was quenched with water (20 mL) and extracted with EA (2 x 20 mL). The organic phase was concentrated at low pressure, and the residue was purified by column chromatography on silica gel (PE:EA=20:l) to give 249-3 as a colorless oil (280 mg, 47.4%) [0518] Compound 249-4 was prepared essentially as described in the preparation of 233. Compound 249 was prepared essentially as described in the preparation of 232 by using 249-4 and 232-5. Compound 249 w^ras obtained as a white solid (7 mg. 13.7%). +ES1MS: m/z 569.0[M+H]⁺.

EXAMPLE 109

Preparation of Compound 250

[0519] Compound 250 was prepared essentially as described in the preparation of

235 by using methyl 4-hydroxy-3-methoxybenzoate and 232-5. Compound 250 was obtained as white solid (19.8 mg. 8.7%). +ESI-MS: m/z 571.0[M+H]⁺.

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EXAMPLE 110

Preparation of Compound 251

Cl Cl

[0520] To a suspension of [IrCl(cod)]2 (18 mg, 0.03 mmol) and sodium carbonate (171 mg, 1.6 mmol) in toluene (10 mL) was added 251-1 (500 mg, 2.68 mmol) and vinyl acetate (457 mg. 5.38 mmol) under Ar. The mixture was stirred at 100 °C for 2 h. The mixture was cooled to r.t., and treated with PE. The precipitate was removed by filtration, and the organic phase was concentrated at low⁷ pressure. The residue was purified by column chromatography on silica gel (PE:EA = 30:1) to give 251-2 (410 mg. 72%).

[0521] TLA (468 mg, 4.1 mmol) was slowly added to anhydrous DCM (5 mL) and EtiZn (4.2 mL, 4.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 10 mins, followed by the addition of CEDE (1.9 g, 7.1 mL). The resulting solution was stirred at 0 °C for 10 mins, and then 251-2 (300 mg. 1.42 mmol) was added. The mixture was allowed to warm to r.t., and stirred at r.t. overnight. The reaction was quenched with sat. NH4CI solution and extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous MgSCfi and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA=20:l) to give 251-3 (210 mg, 65.8%).

[0522] Compound 251-4 was prepared essentially as described in the preparation of 233. Compound 251 was prepared essentially as described in the preparation of 232 by using 251-4 and 232-5. Compound 251 w⁷as obtained as white solid (23 mg, 10.1%). +ESIMS: m/z 559.0[M+H]⁺.

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EXAMPLE 111

Preparation of Compound 252

[0523] Compound 252 was prepared essentially as described in the preparation of

232 by using quinoline-6-carboxylic acid and 232-5. Compound 252 was obtained as a white solid (70 mg. 33%). +ESI-MS:m/z 520.1 [M+H]⁺.

EXAMPLE 112

Preparation of Compound 253

[0524] Compound 253 was prepared essentially as described in the preparation of

232 by using U4-benzo[d]imidazole-5-carboxylic acid and 232-5. Compound 253 was obtained as a white solid (70 mg, 28%). +ESI-MS:m/z 509.1 [M+H]⁺.

EXAMPLE 113

Preparation of Compound 254

[0525] Compound 254 was prepared essentially as described in the preparation of

232 by using benzo[d]thiazole-6-carboxylic acid and 232-5. Compound 254 was obtained as a white solid (38 mg, 33%). +ESI-MS:m/z 525.9 [M+H]⁺.

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EXAMPLE 114

Preparation of Compounds 255, 256 and 398

[0526] To a solution of 255-1 (P g, 27 mmol) and (R)-2-methyloxirane (4.7 g, 82 mmol) in DMF (100 mL) was added K2CO3 (7.4 g, 54 mmol). The mixture was stirred at 80 °C for 3 h. The reaction was quenched with water and extracted by EA (3 x 50 mL). The organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 255-2 (6.5 g, 95%).

[0527] Compound 255-3 was prepared essentially as described in the preparation of 233. Compound 398 was prepared essentially as described in the preparation of 232 by using 255-3 and 232-5. Compound 398 was obtained as a white solid (687 mg. 68%).

[0528] Compound 398 (3 50 mg, 1.14 mmol) was separated via SFC to give two diastereomers: 255 (113 mg) and 256 (107 mg). 255: +ESI-MS:m/z 573.1 [M+H]⁺. 256: +ESI-MS:m/z 573.1 [M+H]⁺.

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EXAMPLE 115

Preparation of Compound 257

[0529] Compound 257-2 was prepared according to the procedure provided in Xu et al.. Angew. Chem. Jnt. Ed. (2011) 50(51):12249-12252. Compound 257 was prepared essentially as described in the preparation of 234 by using 257-2 and 232-5. Compound 257 was obtained as a white solid (51 mg, 23.8%). +ESl-MS:m/z 597.1 [M+H]⁺.

EXAMPLE 116

[0530] Compound 258 was prepared essentially as described in the preparation of

232 by using 3-oxo-3,4-dihydro-2H-benzo[b][l ,4]oxazine-6-carboxylic acid and 232-5. Compound 258 was obtained as a white solid (80 mg. 41%). +ESI-MS:m/z 540.0 [M+H]⁺.

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EXAMPLE 117

Preparation of Compounds 259, 260 and 261

[0531] Compound 259-2 was prepared according to the procedure provided in Chinese Patent No. CN 1869008, published Nov. 29, 2006, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 259-2. Compound 259-3 was prepared according to the procedure provided in Barbayianni et al., J. Org. Chem. (2005) 70(22):8730-8733. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 259-3. Compound 259-4 was prepared essentially as described in the preparation of 235 by using 259-3 and methyl 3-chloro-4-hydroxybenzoate.

Compound 259-4 was obtained as a white solid (4 g. 90%).

[0532] Under H₂ atmosphere, a mixture of 259-4 (4g, 9 mmol) and Pd/C (200 mg) in MeOH (45 mL) was stirred at 30 °C for 10 h. Purification by column chromatography on silica gel provided 259-4 (2 g. 80%). +EST-MS:m/z 269.8[M+H]⁺.

[0533] To a solution of 259-4 and 259-4A (2 g, 7.4 mmol) in THF/H₂O (10 mL/1 mL) was added NaOH (400 mg. 10 mmol) in portions until the starting material was consumed completely. The mixture was neutralized by addition of 2 N HC1 solution. The

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PCT/US2014/051642 mixture was extracted with EA (3 x 40 mL). The organic phase was washed with brine, dried over anhydrous MgSOj and concentrated at low pressure to give 259-5 and 259-5A.

[0534] Compound 259-6 and 261 were prepared essentially as described in the preparation of 232 by using 259-5 and 232-5. Compound 259-6 (100 mg) and 261 (30 mg) were each obtained as a white solid. 261: +ESI-MS:m/z 568.1 [M+H]⁺.

[0535] Compound 259-6 (100 mg. 0.16 mmol) was separated by SFC to give 259 (80 mg, 80%) and 260 (20 mg, 20%). 259: +ESI-MS:m/z 602.1 [M+H]⁺. 260: +ESIMS:m/z 602.1 [M+H]⁺.

EXAMPLE 118

Preparation of Compound 262 ci

[0536] Compound 262 was prepared essentially^ as described in the preparation of

237 by using 2-oxo-2.3-clihydro-lH-benzo[d]imidazole-5-carboxylic acid and 232-5. Compound 262 was obtained as a white solid (58 mg. 24.5%). +ESI-MS:m/z 563.0 [M+H]⁺.

EXAMPLE 119

Preparation of Compounds 264 and 265

[0537] Compounds 264 and 265 were prepared essentially as described in the preparation of 232 by using 1-methyl-lH-bcnzo[d]imidazole-6-carboxylie acid or 1-mcthyllH-benzo[d]imidazole-5-carboxylic acid, and 232-5. respectively. Compounds 264 (47 mg. 26%) and 265 (51 mg, 28%) were each obtained as a white solid. 264: +ESI-MS:m/z 522.9 [M+H]⁺. 265: +ESI-MS:m/z 523.0 [M+H]⁺.

EXAMPLE 120

Preparation of Compound 266 ^F

H HO CF₃ A Y ^N Y ./ ^N \AAri

Cl ° 266 kA/

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PCT/US2014/051642 [0538] Compound 266 was prepared essentially as described in the preparation of

232 by using benzo[d]oxazole-6-carboxylic acid and 232-5. Compound 266 was obtained as a white solid (60 mg, 23%). +ESI-MS:m/z 509.9 [M+H]⁺.

EXAMPLE 12Ϊ

Preparation of Compound 267

[0539] Compound 267 was prepared essentially as described in the preparation of

232 by using 3-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazole-5-carboxylic acid and 2325 as start material. Compound 267 was obtained as a white solid (10.7 mg, 7.6%). +ESIMS:m/z 539.0 [M+H]⁺.

EXAMPLE 122

Preparation of Compound 268

[0540] Compound 268 was prepared essentially as described in the preparation of

232 by using l-methyl-2-oxo-2.3-dihydro-lH-benzo[d]imidazole-5-carboxylic acid and 2325. Compound 268 was obtained as a white solid (14 mg, 8.4%). +ESI-MS:m/z 539.0 [M+H]⁺.

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EXAMPLE 123

Preparation of Compound 269

269-4

269-5

[0541] To a stirred solution of 269-1 (20.0 g, 130.68 mmol) in acetone (400 mL) was added KOH (18.4 g, 15 mmol) and (CH₃)₂SO4 (29.4 mL, 318.9 mmol). The mixture was stirred at r.t. overnight. The solvent was evaporated at low pressure, and the residue was dissolved in hot waler. The pH was adjusted to 9 with 1 N NaOH solution. After cooling to r.t.. the precipitate was filtered off and thoroughly washed with cold EtOAc to give 269-2 as a light yellow' powder (23.66 g, 63.4%). +ESl-MS:m/z 181.8 [M+H]⁺.

[0542] To a solution of 269-2 (14.4 g, 8 mmol) in EtOH (120 mL) was added acetic anhydride (9.0 g, 88 mmol). The mixture was allowed to stir at 50 °C for 2 h. The mixture was cooled to r.t., and neutralized with aqueous NaHCO₃ solution. The mixture was extracted with EA (3 x 60 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1:1) to give 269-3 (15.0 g. 84.1%). +ESI-MS:m/z 223.9 [M+H]⁺.

[0543] To a solution of 269-3 (4.46 g. 20 mmol), PdOAc (0.45 g, 2 mmol) and Cu(OAc)2 (7.26 g, 40 mmol) in 1,2-dichloroethane (150 mL) was added anhydrous CuBr₂(8.93 g. 40 mmol) under N₂ atmosphere. The mixture was stirred at 90 °C for 72 h. After cooling to r.t., the reaction was quenched by water, and filtered through a celite pad. The solution was washed with brine, dried by anhydrous Na₂SC>4 and concentrated at low

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PCT/US2014/051642 pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 1:1) to give 269-4 (6.04 g, 51.3%). +ESl-MS:m/z 303.7 [M+I I]^H.

[0544] To a solution of 269-4 (4.53 g, 15 mmol) in ethanol (60 mL) and water (60 mL) was added NaOH (6.0 g, 150 mmol), and the mixture was stirred at 70 °C overnight. After cooling to 0°C, the mixture was neutralized with 5% aqueous HCI. The precipitate was filtered and concentrated to give 269-5 as a light yellow powder (3.1 g. 82.0%), which was used without further purification. +EST-MS:m/z 247.6[M+H]⁺.

[0545] A mixture of 269-5 (2.44 g. 10 mmol), glycerol (1.5 mL. 20 mmol), and 3-nitrobenzensulfonate (10 g. 45 mmol) were treated with cone. H2SO4 (25 mL) and H₂O (8.3 mL). The mixture was heated at 100 °C for 3 h.. and then stirred at 140 °C for 1 h. The mixture was slowly cooled to 60 °C. Ethanol (15 111L) was added, and the mixture was stirred overnight. The mixture was neutralized with ammonia water, and extracted with EA (3 x 50 111L). The solution was dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by flash column chromatography on silica gel (PE:EA 10:1) to give 2696 (0.50 g, 16.9%). +ESl-MS:m/z 295.9 [M+H]⁺.

[0546] To a stirred solution of 269-6 (0.295 g, 1 mmol) in DMF (3 mL) was added K₂CO₂ (145 mg, 1.05 mmol) and CH3I (149 mg, 1.05 mmol). The mixture was stirred at r.t. overnight, and then concentrated at low pressure. The residue was dissolved in EA (20 mL). The solution was washed with brine, dried over Na₂SO₄ and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PL: LA- 5:1) to give 2697 (216 mg. 70.0%) as a white solid. +ESI-MS:m/z 311.9 [M+H]⁺.

[0547] To a stirred solution of 269-7 (240 g. 0.77 mmol) in methanol (30 mL) was added Pd/C (15 mg). The mixture was stirred at r.t. under H₂ (balloon) for 1 h. The mixture was filtered, and the filtrate was concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA= 5:1) to give 269-8 (101 mg. 56.0%) as a white solid. +EST-MS:m/z 231.9 [M+H]⁺.

[0548] To a solution of 269-8 (0.1 g, 0.44 mmol) in CH3OH (2 ml.) and water (2mL) was added NaOH (80 mg. 2 mmol), and the mixture was stirred at 50 °C for 0.5 h. The mixture was cooled to 0 °C, and the pH was adjusted to 5 using 5% HCI solution. The mixture was extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous

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PCT/US2014/051642 sodium sulfate, and concentrated at low pressure to give crude 269-9 (66 mg, 75.8%) as a white solid, which was used without further purification.

[0549] To a solution of 269-9 (66 mg, 0.325 mmol) in DCM (5 mL) were added DMF (1 drop) and (COC1)₂ (0.23 mL, 1.3 mmol). The mixture was stirred at r.t. for 2 h, and then concentrated at low pressure. The residue was treated with a solution of 232-5 (117 mg. 0.325 mmol) and TEA (0.28 mL) in DCM (5 mL) at 50 °C. The mixture was allowed to stir at r.t. overnight. The mixture was diluted with water, and extracted with EA (3 x 20 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by HPLC to give 269 as a white solid (25 mg. 14.0%). +ESIMS:m/z 550.0 [M+H]⁺.

EXAMPLE 124

Preparation of Compound 270

[0550] Compound 270-2 was prepared according to the procedure provided in Rye et al., Eur. J. Med. Chem. (2013) 60:240-248, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 270-2. To a stirred solution of 270-2 (18.0 g. 89.1 mmol) in acetone (200 mL) were added ethyl 2-bromoacetate (29.6 g, 178.2 mmol) and K₂CO₃ (36.9 g. 270 mmol). The mixture was stirred at 80 °C for 12 h. The mixture was diluted with water and extracted with EA. The organic layers were dried over anhydrous sodium sulfate, and concentrated in vacuum. The residue was purified by column chromatography on silica gel to give crude 270-3 (25 g yield: 98%).

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PCT/US2014/051642 [0551] To a solution of 270-3 (11 g, 38.2 mmol) in anhydrous THF (100 mL) was added Ti(i-PrO)_i (10.85 g. 38.2 mmol) under N₂ at 0 °C, and then EtMgBr (34.4 mL, 103.14 mmol) was added dropwise. The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with EA (3 x 60 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 270-4 (4.2 g. 40.4%).

[0552] To a solution of 270-4 (2.5 g, 9.19 mmol) in DCM (20 mL) were added DHP (1.54 g, 18.38 mmol) and TsOH (158.2 mg, 0.92 mmol). The mixture was stirred at r.t. overnight. The reaction was quenched with water, and extracted with DCM. The organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 270-5 as a white solid (2.6 g, yield: 74.0%).

|0553] To a solution of 270-5 (1.5 g, 4.21 mmol) in anhydrous THF (15 mL) was added w-BuLi (2.0 mL. 5.0 mmol) at -78 °C dropwise. After the mixture was stirred at -78 °C for 0.5 h, CICOOCH3 (2.39 g. 25.28 mmol) was added in one portion. The mixture was stirred at -78 °C for 1 h, and then diluted with EA (50 mL) and washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to generate 270-6 as a w'hite solid (820 mg. yield: 58%).

[0554] To a stirred solution of 270-6 (410 mg. 1.22 mmol) in EtOH/H₂O (3:1, 10 mL) was added NaOH (195 mg, 4.88 mmol), and the mixture was stirred at 50 °C for 1 h. The mixture was diluted with water and extracted with EA. The pH of aqueous layers was adjusted to 4.0 by adding 5% HC1 solution. The aqueous phase was extracted with EA. The organic layers were dried over anhydrous sodium sulfate and concentrated in vacuum to give crude 270-7 (198 mg).

[0555] To a solution of 270-7 (200 mg, 0.62 mmol) in DMF (15 mL) were added DIPEA (240 mg, 1.86 mmol) and HATU (236 mg, 0.62 mmol). The mixture was stirred at r.t. for 30 mins, and then 232-5 (226 mg, 0.62 mmol) was added. The mixture was stirred at r.t. for 2 h. and then diluted with water and extracted with EA (3 x 20 mL). The organic layer

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PCT/US2014/051642 was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel to give 270-8 (250 mg, 60.4%).

[0556] To a solution of 270-8 (250 mg, 0.37 mmol) in EtOH (10 mL) was added PPTS (19.4 mg. 0.075 mmol). The mixture was stirred at 70 °C for 2 h, and then diluted with EA (50 mL) and washed with brine. Lhe organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by prep-HPLC to give 270 as a white solid (80 mg, 37.0%). +ESI-MS:m/z 585.1 [M+H]⁺.

EXAMPLE 125

Preparation of Compounds 271, 272 and 314

[0557] A 1 L round bottom flask was charged with a mixture of 271-1 (15 g. 86.71 mmol). (3-chloro-4-fluorophenyl) boronic acid (15 g. 86.03 mmol). [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium(TT) (1.0 g, 1.37 mmol) and K2CO3 (23.7g, 172 mmol) in dioxane/LLO (450 mL/50 mL) under N2 atmosphere. Lhe mixture was heated to 100 °C for 2 h. The mixture was cooled to r.t. and dioxane was evaporated under reduced pressure. The residue was diluted with EA and water. The organic layer was dried

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PCT/US2014/051642 over anhydrous Na^SOj and concentrated under reduced pressure. Chromatography of the residue (PE:EtOAc 100:1 to 40:1) afforded 271-2 as a white solid (11 g, 47.8%).

[0558] To a solution of 271-2 (7.2 g, 26.9 mmol) in toluene (200 mL) was added MeMgBr (27 mL. 81mmol) in 5 mins. The solution was stirred for 30 mins at r.t. Ti(OiPr)4 (8 mL. 27.3 mmol) was added slowly at r.t. The solution was bathed in 100 °C oil and stirred for 20 mins. The mixture was cooled to r.t.. and the reaction was quenched with a sat. aq. Na2CO₃ solution. The mixture was separated by filtration, and the cake was washed with EA. The organic phase was concentrated to dryness, and crude 271-3 (7.0 g, brown oil) was used directly in the next step.

[0559] To a solution of 271-3 (7.0 g. 23.4 mmol) in toluene (100 mL), Et₃N (7.09 g, 70.2 mmol) and Boc₃O (5.6 g, 25.7 mmol) were added at r.t. The solution was bathed in 100 °C oil and stirred for 3 h. The solution was cooled to r.t., and separated between EA (300 mL) and water (200 mL). The organic phase was washed with brine and dried over NihSOi. The organic phase was concentrated, and the residue was purified by chromatography on silica gel (PE:EA 20:1-10:1) to give 271-4 as a yellow solid (7.05 g, 75.5%). +ES1-MS: m/z 398.9 [M+H]⁺.

[0560] To a solution of 271-4 (7.0 g. 17.5 mmol) in EtOH (70 mL) were added I<2CO₃ (3.62 g, 26.2 mmol) and potassium trifluoro(vinyl)borate (2.8 g, 21.0 mmol) at r.t. Pd(dppf)C12 (256 g, 0.35 mmol) was added under N? atmosphere. The mixture was bathed in 100 °C oil and stirred for 3 h. The solution was concentrated at low pressure, and the residue was separated between EA (100 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous Na₃SO4 and concentrated at low pressure. The residue was purified by chromatography on silica gel (PE:EA 20:1-10:1) to give 271-5 as a yellow oil (6.1 g, 89.3%). +EST-MS: m/z 391.0 [M+H]⁺.

[0561] A solution of 271-5 (6.1 g, 15.6 mmol) in DCM (150 mL) was bubbled with O₃ at -78 °C until the solution turned blue. The solution was then bubbled with N₃ until the blue colour disappeared. PPh₃ (4.9 g, 18.72 mmol) was added at -78 °C, and stirred for 2 h at -78 °C. The mixture was concentrated at low pressure, and the residue was purified by chromatography on silica gel (PE:EA 10:1-5:1) to give 271-6 as a white solid (4.8 g. 78.4%).

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PCT/US2014/051642 [0562] To a solution of 271-6 (4.86 g, 12.38 mmol) in dry DMF (25 mF) was added TMSCFj (4.4 g, 31.0 mmol). The mixture was cooled down to -78 °C, and TBAF (1M in THF. 7.3 mF, 7.3 mmol) was added dropwise. The mixture was allowed to gradually warm to r.t., and stirred for 0.5 h. The mixture was diluted with water and EtOAc. The organic layers was dried over anhydrous Na₂SO4 and concentrated under reduced pressure. Chromatography of the residue (PE:EtOAc 100:0 to 80:20) afforded 271-7 (4.1 g. 72%).

[0563] To a stirred solution of 271-7 (4.1 g, 8.86 mmol) in dry DCM (45 mL) was added Dess-Martin periodinane (4.96 g, 17.7 mmol). The mixture was stirred at r.t. for 10 h. The mixture was concentrated under reduced pressure and chromatography of the residue (PEiEtOAc 100:0 to 70:30) afforded 271-8 (3.8 g, 93%).

[0564] To a solution of 271-8 (3.8 g. 8.25 nnnol) in MeNO₂ (10 mL) was added Et₃N (2 mL, 14mmol), and the mixture was stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure, and the residue was dissolved in co-solvent of EtOH:H₂O(50 mL:5 mL). The mixture was treated with iron powder (1.85 g, 33mmol) and NH4CI (1.8 g, 33mmol), and then heated to 80 °C for 2 h. After filtration, the solution was concentrated under reduced pressure. The residue was purified by chromatography to give 271-10 (2.5 g, 61.7%). +ES1-MS: m/z 491.9 [M+H]⁺.

[0565] A 100 mL round bottom flask was charged with a solution of 4cyclopropoxy-3-methoxybenzoic acid (208 mg, 1.0 mmol), DIPEA (193 mg, 1.5 mmol) and HATU (380 mg. 1.0 mmol) in anhydrous DMF (10 mL). The mixture was stirred at r.t. for 30 mins. Compound 271-10 (490 mg, 1.0 mmol) was added in one portion, and the mixture was stirred at r.t. for 2-3 h. The mixture was diluted with EA and water, and the organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 1:1) to give 271-11 as a pale yellow oil (610 mg. 88%).

[0566] A 50 mL round bottom flask was charged with a solution of 271-11 (610 mg, 0.88 mmol) in EA (10 mL). The solution was treated with HC1 in EA (10 mL, 4.0 M). The mixture was stirred at r.t. for 1-2 h. The mixture was concentrated at low pressure to give crude 314 (550 mg).

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PCT/US2014/051642 [0567] Compound 314 (550 mg) was separated via SFC separation to give two enantiomers. The two enantiomers were treated with 2 Μ IIC1 in EA and then concentrated to give 271 (120 mg) and 272 (124 mg). 271: +ESI-MS:m/z 582.1 [M+H]⁺. 272: +ESIMS:m/z 582.1 [M+H]⁺.

EXAMPLE 126

Preparation of Compound 273

[0568] Compound 273 was prepared essentially as described in the preparation of compound 272 by 273-1 and 273-2. Compound 273 was obtained as a white solid (41 mg, 52.2%). +ESl-MS:m/z 554.0 [M+H]⁺.

EXAMPLE 127

Preparation of Compounds 274-285 [0569] The following compounds in Tabic 1 were prepared essentially as described in the preparation of 272 by using the listed acid and amine.

Table 1

Compound	Acid	Amine	Yield and +ESl-MS:m/z
<\/^F r Ί η v^0H \ ί £ Λ. N X N A AT _?A Al	benzo[d][1.3]dioxole-5-	773-7	32 mg, 58.8%
° 274 A	nh₂	carboxylic acid		539.9 [M+H]⁺

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Compound	Acid	Amine	Yield and +ESI-MS:m/z

0	fL^f ⁰ 275	,, l·	< /A/ '¥%	F ΌΙ	2.2- di fluoro benzo [d][l ,3]dioxole -5-carboxylic acid	273-2	38 mg, 46.5% 576.0 [M+H]⁺
			nh₂
N Cl—( S'	fA^fR H X°^H _r<->L⁷--_Y-^ro L 276	,γ	F ΌΙ	2-chlorothiazole-5- carboxylic acid	273-2	30 mg, 54.5% 536.9 [M+H]⁺
			nh₂
	φ			F
/^N s \	h Loh		Xi
	-,/^N-Lz^N ¥ li		Cl	thiazole-4-carboxylic acid	273-2	32 mg, 64.0%
	⁰ 277		nh₂			502.9 [M+H]⁺

	fA^f			,F
(1	H \^0H		γυ
			Cl	thiazole-5-carboxylic acid	273-2	18 mg, 36.0%
	⁰ L 278 \|					502.9 [M+H]⁺
		nh₂
/^N S	^fV H V°^H n. LL /1% ¥i ii		^F >31	2-methylthiazole-4-	273-2	23 mg, 45 %
	o L 279	χί	nh₂		carboxylic acid	517.0 [M+H]⁺

Cl An s X	^fV h\^oh. , ^N LL ^N Π Ti	/3	„F >31	2-chlorothiazole-4-	273-2	24 mg, 45 <>
	o L 280		nh₂		carboxylic acid	537.0 [M+H]⁺

0	Cl
^HNvT	A LLnJ o	F OH ¥ \1	I ΌΙ	3-chloro-4-((2-oxopyrrolidin- 3-yl)oxy)benzoic acid	273-2	28 mg. 45 % 629.0 [M+H]⁺
	281		XnH₂

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Compound	Acid	Amine	Yield and +ESI-MS:m/z
Cl ^f4/^fvZ \ X H \°^H ⁰ L· 282 ]	/X ^xnh₂	3-chloro-4- cyclopropoxybcnzoic acid	273-2	20 mg, 34 % 585.9 [M+HJ*
hnVVI h^F^oh fV^F o ²⁸³ JL '%'NH₂	(Si-3-methoxy-4-((2oxopyrrolidin-3yl)oxy)benzoic acid	273-2	28 mg, 45 % 625.1 [M+H]⁺
• · o ° r 1 hF₃C OH o X 284	X¥^f ^xnh₂	4-(cyclopropylmethoxv)-3methoxybenzoic acid	273-2	30 mg. 68.2% 596.1 [M+H]⁺
hnV/i A> rr^F Ό υγ+ν“<Λ\ o XX ²⁸⁵ X ^7'NH₂	<7?)-3-methoxy-4-((2oxopvrrolidin-3 yl)oxy)benzoic acid	273-2	28 mg, 45 % 625.0 [M+H]⁺

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EXAMPLE 128

Preparation of Compound 286

286-5 ²8⁶·⁷ 286-8 286-9

[0570] Compound 286-2 was prepared according to the procedure provided in PCT Publication No. WO 2009/005638, published Jan. 8, 2009, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 286-2.

[0571] To a solution of 286-2 (1.83 g, 7 mmol) in THF (15 mL) was added nBuLi (7 mL, 2.5 M in THF) at -78 °C. After 5 mins, TMEDA (1,624g, 14 mmol) was added at -78 °C. The solution was warmed slowly to -30 °C. and stirred for 30 mins at -30 °C. The solution was cooled to -78 °C and oxirane (0.7 mL, 14 mmol) was added. The solution was stirred at -78 °C for 2 h.. and stirred overnight at r.t. The reaction was quenched with IEO and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous NirSOi and concentrated at low⁷ pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 286-3 (0.7 g, 32.7 %).

[0572] To a solution of 286-3 (4.5 g, 14.7 mmol) in DCM (100 mL) was added TEA (4.45 g, 44.1 mmol). After cooled to 0 °C, MsCl (3.36 g, 29.4 mmol) was added slowly. The solution was stirred for 30 mins. The reaction was quenched with H?O, and extracted with DCM (3 x 100 mL). The organic phase was washed with brine, dried over

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PCT/US2014/051642 anhydrate sodium sulfate and concentrated at low pressure to give crude 286-4 (5.6 g, 99.2%). +ESI-MS:m/z 384.8 [M+I I]¹.

[0573] To a solution of 286-4 (5.6 g, 14.5 mmol) in DMF (50 mL) was added K2CO3 (4.02 g, 29.2 mmol). The mixture was heated up to 50-60 °C. and stirred for 1 h. The solution was cooled to r.t., poured into cold water and extracted with EA (2 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated at low pressure. The residue was purified by chromatography (PE:EA 10:1) to give 286-5 (3.1g. 74.3%).

[0574] To a solution of 286-5 (1.68 g. 5.83 mmol). 286-6 (860 mg. 5.83 mmol) and K2CO3 (1.61 g, 11.66 mmol) in MeOH (50 mL) was added Pd(dppf)C12 (426 mg. 0.583 mmol). The mixture was degassed and then refilled with N₂ (3 times). The mixture was stirred under nitrogen at 70 °C for 15 h. and then cooled to r.t., and extracted with EA (3 x 50 111L). The organic phase was washed by brine, dried over anhydrous Na₂SC>4 and concentrated at low⁷ pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 286-7 as a white solid (1.2 g, 70%).

[0575] To a solution of 286-7 (2.94 g, 10 mmol) in DCM (50 mL) were added NMO (2.4 g, 20 mmol) and ()s() | (500 mg, 0.2 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. aq. Na₂SO3. and stirred for 2 h. The mixture was extracted with DCM (2 x 100 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 3:1) to give 286-8 (2.94 g. 89.6%). +ESI-MS:m/z 328.9 [M+H]⁺.

[0576] To a solution of 286-8 (3.28 g. 10 mmol) and TEA (4.45 g, 44.1 mmol) in DCM (20 mL) was added MsCl (2.2 g, 20 mmol) slowly at 0^(>C. The solution was stirred for 30 mins, and then diluted with DCM (20 mL). The solution was washed with brine and dried over anhydrous sodium sulfate. The organic phase was concentrated at low⁷ pressure to give crude 286-9 (4.06 g, 100.0%).

[0577] A solution of 286-9 (4.0 g, 10 mmol) in ammonia water and ethanol (10 ml.: 10 mL) in a seal tube was stirred for 1 h at r.t. The solution was heated to 40 °C for 15 h.

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The mixture was concentrated to dryness under reduced pressure to give crude 286-10 (1.6 g, 50%), which was used without purification. +ESI-MS:m/z 327.9 [M+11]⁺.

[0578] To a solution of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (214 mg, 1 mmol), HATU (456 mg. 1.2 mmol) and DIPEA (258 mg, 2 mmol) in anhydrous DMF (5 mL) was added 286-10 (327 mg, 1 mmol) at 25 °C. The solution was stirred for 2 h at 25 °C. The reaction was quenched by a sat. aq. NaHCCfi solution (40 mL), and then extracted with EA (2 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 3:1) to give 286-11 (201 mg, 38.2%). +ESI-MS:m/z 524.0 [M+H]⁺.

[0579] To a solution of 286-11 (150 mg. 0.3 mmol). (3-chloro-4fluoiOphenyl)boronic acid (105 mg, 0.6 mmol) and K2CO3 (84 mg, 0.6 mmol) in dioxane (6 111L) was added Pd(dppf)C12 (22 mg. 0.03 mmol). The mixture was degassed and then refilled with N2 (3 times). The mixture was heated to 120 °C by microwave under N? for 2 h. The solution was cooled to r.t. and diluted with EA (20 mL). The solution was washed with brine, dried over anhydrous NaoSCfi and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 1:1) to give 286-12 (123 mg, 65%).

[0580] To a solution of 286-12 (123 mg, 0.2 mmol) in DCM (2 mL) was added TFA (4 mL) at r.t. The mixture was stirred for 30 mins, concentrated to dryness and dissolved in EA (20 mL). The solution was washed with a sat. NaHCCL solution. The organic layer was washed with brine, dried over anhydrous NaiSCfi and concentrated at low pressure. The residue was purified by prep-HPLC to give 286 (80 mg. 77.6%) as a yellow solid. +ESIMS:m/z 518.1 [M+H]⁺.

EXAMPLE 129

Preparation of Compound 287

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PCT/US2014/051642 [0581] Compound 287 was prepared essentially as described in the preparation of 286 by using 7-fluoro-3-(4,4.5,5-tetramethyl-1.3,2-dioxaborolan-2-yl)-l-((2(trimethylsilyl)cthoxy)mcthyl)-lH-indole and 287-1. Compound 287 was obtained as white solid. +ESI-MS:m/z 507.9 [M+H]⁺.

EXAMPLE 130

Preparation of Compounds 288 and 289

[0582] To a solution of 135 (400 mg, 0.80 mmol) in THF (10 mL) was added MeMgBr (3 mL, 1.3 N in THF) under N?. The mixture was stirred at r.t. for 1 h under N2. The reaction was quenched with sat. aq. NH4CI and extracted with EA (3 x 20 mL). The combined organic layers were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by prep-HPLC to give 288-1 (150 mg).

[0583] Compounds 288 (39 mg) and 289 (41 mg) were obtained by SFC separation of 288-1. 288: +ESI-MS:m/z 519.3 [M+H]⁺. 289: +ESI-MS: m/z 519.3 [M+H]⁺.

EXAMPLE 131

Preparation of Compound 290

[0584] To a solution of 286 (400 mg, 0.77 mmol) in DCM (20 mL) was added MnCE (336 mg, 3.86 mmol) at r.t. The mixture was stirred for 2 h. The precipitate was removed by filtration, and the filtrate was concentrated at low pressure. The residue was purified by prep-HPLC to give 290 (150 mg, 37.5%) as a yellow solid. +ESI-MS:m/z 515.9 [M+H]⁺.

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EXAMPLE 132

Preparation of Compounds 291 and 292

[0585] Compounds 291 and 292 were prepared essentially as described in the preparation of 288 and 289 by using 291-1. Compound 291 (31 mg) and 292 (30 mg) were obtained as white solids. 291: +ESl-MS:m/z 524.1 [M+H]⁺. 292: +ESl-MS:m/z 524.1 [M+H]⁺.

EXAMPLE 133

Preparation of Compounds 293 and 294

[0586] Compound 286 (60 mg) was separated via SFC separation to obtain two enantiomers: 293 (24 mg) and 294 (22 mg). 293: +ESI-MS:m/z 517.9 [M+H]⁺. 294: +ESTMS:m/z 517.9 [M+H]⁺.

EXAMPLE 134

Preparation of Compounds 295 and 296

[0587] Compound 290 (65 mg) was separated via SFC separation to obtain two enantiomers: 295 (21 mg) and 296 (18 mg). 295: +ESl-MS:m/z 515.9 [M+H]⁺. 296: +ES1MS:m/z 515.9 [M+H]⁺.

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EXAMPLE 135

Preparation of Compound 297

[0588] To a solution of 297-1 (1.4 g, 5.0 mmol) and 2-chloro-N-methoxy-Nmethylacetamidein (700 mg. 5.0 mmol) in THF (20 mL) was added /-PrMgCl (3 mL, 2.0 M in THF) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extrcted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na?SO4 and concentrated in vacuum. The residue was purified by column chromatography on silical gel to give 297-2 (1.0 g, 87%). +ESIMS:m/z 232.0 [M+H]⁺.

[0589] To a solution of 297-2 (460 mg, 2.0 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 mL, 0.5 M in THF) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4 and concentrated in vacuum. Compound 297-3 was used without furthur purification.

[0590] Compound 297 was prepared essentially⁷ as described in the preparation of 286 by⁷ using 297-3. Compound 297 was obtained as white solid (98 mg). +ESI-MS:m/z 548.3 [M+H]⁺.

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EXAMPLE 136

Preparation of Compound 298

[0591] Compound 298-2 was prepared according to the procedure provided in PCT Publication No. WO 2009/016460, published Feb. 5, 2009. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 2982. To a solution of 298-2 (1.8 g, 8.3 mmol) in DCM (10 mL) was added DAST (2 mL) dropwise at 0°C. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaHCOs solution at 0 °C and extracted with EA (3 x 30 mL). The combined organic layers were washed by brine, dried over anhydrous Na₂SC>4 and concentrated in vacuum. The residue was purified by column chromatography on silica gel column (PE:EA 30:1) to give 298-3 as a white solid (1.4 g. 77.8%).

[0592] To a solution of 298-3 (1.4 g. 6.4 mmol) in THF (10 mL) was added nBuLi (3.3 mL, 2.5 N in hexane) dropwise at -78 °C under N₂. The mixture was stirred at -78 °C for 30 mins. 2-isopropoxy-4.4,5.5-tetramethyl-1.3,2-dioxaborolane (1.6 g, 9.4 mmol) was added at -78 °C, and the mixture was allowed to warm to r.t.. and stirred 10 mins. The reaction was quenched with sat. NH4CI solution and extracted with EA. The combined organic solutions were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 50:1) to give 298-4 as an oil (1.0 g, 58.9%).

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PCT/US2014/051642 [0593] Compound 298 was prepared essentially as described in the preparation of

286 by using 298-4. Compound 298 was obtained as a white solid (70 mg). +ESI-MS:m/z 555.1 [M+H]⁺.

EXAMPLE 137

Preparation of Compound 299

[0594] Compound 299 was prepared essentially as described in the preparation of

288 and 289 by using 298 and cyclopropylmagnesium bromide. Compound 299 (30 mg) was obtained as a white solid. +ESI-MS:m/z 597.2 [M+H]⁺.

EXAMPLE 138

Preparation of Compounds 300 and 301

Ό

[0595] Compound 229 (28 mg, 0.047 mmol) was separated via SFC separation to give two enantiomers: 300 (3.8 mg) and 301 (4.5 mg) as white solids. 300: +FSI-MS:m/z 595.0 [M+H]⁺. 301: +FSl-MS:m/z 595.0 [M+H]⁺.

EXAMPLE 139

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PCT/US2014/051642 [0596] To a solution of 335-1 (5.2 g, 20 mmol) in THF (50 mL) was added nBuLi (16 mL, 20mmol, 2.5M) at -78 °C under N₂. After stirred at -78^l’C for 0.5 h, a solution of I₂ (5.1g 20 mmol) in THF (25 mL) was added slowly. The mixture was stirred at -78 °C for 1 h. The reaction was quenched with water and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 335-2 (7.5 g. 95 %). +ESI-MS: m/z 388.9 [M+H]⁺.

[0597] To a solution of 335-2 (3.88 g, 10.0 mmol) in DMF (50 mL) was added sodium hydride (480 mg, 10 mmol, 60% in the mineral oil) at r.t. The mixture was stirred for 0.5 h and 3-chloro-2-methylprop-l-ene (1.0 g. 11 mmol) was added dropwise. The mixture was stirred for 2 h. The reaction was quenched with water and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give crude 335-3 (4.4 g. 99%), which was used without further purification.

[0598] Under N₂ atmosphere, a mixture of 335-3 (4.4 g, 10 mmol). LiCl (420 mg, 10 mmol), sodium formate (1.36 g, 20 mmol) and Pd(OAc)₂ (111 mg, 0.1 mmol) in DMF (95 mL) was stirred at 100 ^l’C for 2 h. After cooling to r.t, the mixture was diluted with EA (50 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 335-4 (1.5 g. 50%). +ESI-MS: m/z 316.9 [M+H]⁺.

[0599] Under N₂ atmosphere, a mixture of 335-4 (1.5 g. 5 mmol). tributyl(lethoxyvinyl)stannane (3.6 g. 10 mmol) and Pd(dppf)Cl₂ (180 mg, 0.25 mmol) in toluene (15 mL) was stirred at 140 °C for 0.5 h. After cooling to r.t., the mixture was concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 335-5 (1.5 g. 88%). +ESI-MS:m/z 352.9 [M+H]⁺.

[0600] To a solution of 335-5 (1.5 g, 1.35 mmol) in THF/H₂O (30mL/lmL) was added NBS (2.70 g. 15 mmol) in portions. The mixture was diluted with water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 335-6 (1.5 g, 75 %).

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PCT/US2014/051642 [0601] To a solution of 335-6 (400 mg, 1.0 mmol) in DMF (5mL) was added CF3TMS (1 mL) and LiOAc (10 mg 0.02 eq.). After addition, the mixture was stirred at r.t. until 335-6 was consumed. Lhe mixture was treated with ammonia water (5 mL), and then stirred at r.t. for 0.5 h. The mixture was diluted with EA (50 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 1:1) to give 335-7 (205 mg, 50%). +ESI-MS:m/z 410.0 [M+H]⁺.

[0602] Compound 335 was prepared essentially as described in the preparation of 286 by using 4-cyclopropoxy-3-methoxybenzoic acid and 335-7. Compound 335 was obtained as a white solid (25 mg). +EST-MS:m/z 594.1 [M+H]⁺.

EXAMPLE 140

Preparation of Compound 302

302-1 302.2 302-3 302-4

[0603] To a stirring mixture of 302-1 (460 mg. 1.6 mmol) in DMF (2 mL, deoxygenated prior to use) were added PdCLiPPhs)? (114 mg, 0.16 mmol) and tributyl(vinyl)stannane (500 mg, 1.6 mmol). Lhe reaction was carried out under microwave irradiation at 80 °C for 2 h. Lhe mixture was cooled to r.t. and diluted with EtOAc. Lhe mixture was washed with brine:water:NaHCO3. Lhe mixture was dried over MgSO₄, filtered and concentrated under reduced pressure. Crude 302-2 was purified via a silica gel column. LCMS: m/z 186.05 [M+H]⁺.

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PCT/US2014/051642 [0604] To a stirring mixture of 302-2 (170 mg. 0.915 mmol) in DMF (3mL) was added Nall (37 mg, 0.915 mmol). The mixture was stirred for 10 mins before allyl bromide (96 pL, 1.09 mmol) was added. The mixture was stirred for 1 h at r.t., and then diluted with EtOAc and a 10% NaHCO₃ aq. solution. The mixture was worked-up with EtOAc. The crude was purified via a silica gel column to afford 302-3 as a yellow oil. LCMS: m/z 226.05 [M+H]⁺.

[0605] To a stirring mixture of 302-3 (100 mg, 0.44 mmol) in CH2CI2 at r.t. (3.5 mL) was added benzylidene-bis(tricyclohexylphosphine) dichlororuthenium (12 mg, 0.014 mmol). The mixture was stirred for 3 h and then concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-4 as a tan solid. LCMS: m/z 198.0 [M+H]⁺.

[0606] To a stirring mixture of 302-4 (70 mg. 0.35 mmol) in DME (2 mL. deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronic acid (74 mg, 0.43 mmol). PdCl₂(PPh₃)₂, a solution of CS2CO3 (0.4 mL. 2.65 M). The mixture was carried out under micro wave irradition at 110 °C for 1 h and then diluted with EtOAc and water. A normal aqueous workup was followed. The crude was purified via a silica gel column to afford 302-5 as a white solid. LCMS: m/z 292.0 [M+H]⁺.

[0607] To a stirring mixture of 302-5 (70 mg, 0.24 mmol) in CFECl? (2 mL) at r.t. were added NaHCO₃ (114 mg, 1.7 mmol) and Dess-Martin periodinane (509 mg, 1.2 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with 5% NallSO; and sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (Na₂SO4), filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-6. LCMS: m/z 290.0 [M+H]⁺.

[0608] To a stirring mixture of 302-6 (40 mg. 0.138 mmol) in THF (2 mL) were added K₂CO₃ and nitromethane (25 mg, 0.42 mmol). The mixture was stirred overnight at r.t. The reaction was diluted with EtOAc and quenched with water and brine. The aqueous layer was extracted with EtOAc (2 x 25mL). The crude was purified via a silica gel chromatography to afford 302-7 as a while solid; LCMS: m/z 351.0 [M+H] .

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PCT/US2014/051642 [0609] To a stirring mixture of 302-7 (55 mg, 0.158 mmol) in EtOAc (0.5 mL) was added SnCl₂. 211₂O (106 mg, 0.47 mmol). The mixture was heated at reflux for 1 h. The mixture was cooled and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 302-8 as a colorless oil. LCMS: m/z 321.0 [M+H]⁺.

[0610] To a stirring mixture of 4-(2-fluoroethoxy)-3-methoxybenzoic acid (33.8 mg, 0.156 mmol) in DMF (0.5 mL) were added HATU (59.3 mg, 0.156 mmol) and DIPEA (40 mg, 0.26 mmol). The mixture was stirred at r.t. for 10 mins. Compound 302-8 (50 mg. 0.156 mmol) in DMF (0.5 mL) was added, and then the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCOj (10 mL). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 302-9 as a white solid. LCMS: m/z 517.10 [M+H].

[0611] To a stirring mixture of 302-9 (30 mg. 0.058 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane (172 mg. 0.41 mmol). The mixture was stirred at r.t. for 1 h and the reaction quenched with 5% NaFISO; and a sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (NaiSOq), filtered and concentrated under reduced pressure. The crude product was purified via HPLC to afford 302 as a white solid. LCMS: m/z 515.05 [M+H],

EXAMPLE 141

Preparation of Compound 303

[0612] Compound 303 was synthesized by reacting 302 under hydrogenation reaction conditions using Pd/C in EtOAc/EtOH. LCMS: m/z 517.1 [M+H],

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EXAMPLE 142

Preparation of Compound 304

mixture of 3-methoxy-4-(2-((4stirring methoxybenzyl)oxy)ethoxy)benzoic acid (40 mg, 0.12 mmol) in DMF (0.5 mL) were added HATU (36 mg. 0.096 mmol) and DIPLA (25 mg. 0.192 mmol). The mixture was stirred at r.t. for 10 mins. Compound 304-1 (31 mg, 0.096 mmol) in DMF (0.5 mL) was added, the mixture was stirred for 10 mins. The reaction was quenched with 10% NallCO; (3 mL). The mixture was diluted with DCM and a normal aqueous workup with DCM was followed. The crude was purified via prep- HPLC to afford 304-2 as a white solid. LCMS: m/z 635.1 [M+H].

[0614] To a stirring mixture of 304-2 (30 mg, 0.047 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane (200 mg, 0.47 mmol). The mixture was stirred at r.t. for 1 h, and the reaction was quenched with 5% Nal ISO ; and a sat. NaHCOj solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (NajSOj. filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 304-3 as a white solid; LCMS: m/z 633.15 [M+H]⁺.

[0615] To a stirring mixture of 304-3 (20 mg. 0.031 mmol) in EtOH/EtOAc (1:1.

mL) was added Pd/C (10 mg). The mixture was reacted under H2 balloon. The mixture

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PCT/US2014/051642 was filtered through a plug of celite, and the filtrate was concentrated under reduced pressure. Crude 304-4 was used without further purification; LCMS: m/z 635.15 [M+I I]⁺.

[0616] To a stirring mixture of 304-4 in DCM (1 mL) at 0 °C was added TFA (0.3 mL) dropwise. The mixture was stirred at r.t. for 10 mins and then diluted with EtOAc. The reaction was quenched sat. NaHCOs. The aqueous layer was extracted with EtOAc. dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified via prep-HPLC to afford 304 as a white solid. LCMS: m/z 515.10 [M+H]⁺.

EXAMPLE 143

Preparation of Compound 305

305-1 305-2 305-3 305-4

O

[0617] To a stirring mixture of 305-1 (500 mg. 1.75 mmol) in DMF (8.8 mL) at 0 °C was added NaH (144 mg. 3.6 mmol). The mixture was stirred at 0 °C for 5 mins. Allyl bromide (222 mg. 1.75 mmol) was added, and the mixture was stirred at 0 °C for 20 mins. The mixture was warmed to r.t. and stirred for 5 mins. The mixture was diluted with EtOAc and quenched with water. The aqueous layer was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel chromatography to afford 305-2. LCMS: m/z 325.9 [M+H]⁺.

[0618] To a stirring mixture of 305-2 (280 mg, 1.4 mmol) and AIBN (23 mg. 0.14 mmol) in toluene (3.5 mL) under Ar at reflux was added a solution of tributvltin hydride (407 mg, 1.4 mmol) in toluene (1 mL) dropwise over 5 mins. The mixture was stirred at reflux for 2 h. and then concentrated under reduced pressure. The crude was purified via a silica gel column to afford 305-3 as a colorless oil. LCMS: m/z 200.05 [M+I I]⁺.

[0619] Lo a stirring mixture of 305-3 (170 mg, 0.85 mmol) in DME (2.4 mL, deoxygenated prior to use) were added (3-chloro-4-fluorophenyl)boronic acid (163 mg, 0.94

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PCT/US2014/051642 mmol), PdChCPPhsfr (93 mg, 0.13 mmol) and a solution of CS2CO3 (0.6 mL, 4.25 M). The reaction was carried out under microwave Tradition at 110 °C for 1 h. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 305-4 as a white solid. LCMS: m/z 294.0 [M+H], [0620] Compound 305-7 was prepared in three steps similarly to the methods described for the synthesis of 302. Coupling of 305-7 with 3-methoxy-4-(2-((4methoxybenzyl)oxy)ethoxy)benzoic acid followed by alcohol oxidation and deprotection afforded 305. LCMS: m/z 515.10 [M+H]⁺.

EXAMPLE 144

[0621] To a stirring mixture of 306-1 (30 mg, 0.047 mmol) in THF (0.45 mL) at r.t. under Ar was added cyclopropyl magnesium bromide (1.9 mL. 0.95 mmol). The mixture was stirred for 30 mins and then diluted with EtOAc. The reaction was quenched with a sat. NH4CI solution. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel column to afford 306-2. LCMS: m/z 675.20 [M+H]⁺.

[0622] To a stirring mixture of 306-2 (30 mg, 0.052 mmol) in DCM (1 mL) was added TFA (0.2 mL) at r.t. The mixture was stirred for 10 mins, and then quenched with a cold sat. NallCOj solution. The aqueous solution was extracted with DCM. The combined organic layers were washed with brine, dried over anhydrous Na^SCf, and concentrated under reduced pressure. The crude was purified via prep-HPLC to afford 306 as a white solid. LCMS: m/z 555.10 [M+H]⁺.

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Tabic 2

EXAMPLE 145

Preparation of Compounds 307-312

Example Method	No.	Structure	LCMS:m/z
Compound 306	307	Y ^HO ΤΊ η °^H ΠΓ ^N Υ^γ ^N γ^^υ i ⁰ Uo	529.10 [M+H]⁺
Compound 306	308	Y Y <1 .F ^H0 \ 11 η \^OH \ H o γ o	557.15 [M+H]⁺
Compound 306	309	Y ο Y ,f HO \ il H ^OH \ H ^{N Ν}<Α+Αγ\| ⁰ ^Uy	557.15 [M+H]⁺
Compound 306	310	Y _Ηη·' Υ,+ V ^H0 1 1 ^H \ oh \ H ^Y ^N ^^Y ^N γ^Υι ° k}°	543.15 [M+lY
Compound 298	311	Y ^ho^°yS h ° ΥγΝγΐι ο Y	YY^^F ^JyYoi ^;::O	543.15 [M+H]⁺
Compound 306	312	Y T1 ^h /°^H YY^NYYi o	YY^^F ⁴γ''’^^/Όΐ	585.15 [M+H]⁺

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EXAMPLE 146

Preparation of Compound 313

[0623] To a stirring mixture of 313-1 (45 mg, 0.092 mmol) in THF(1 mL) at r.t.

under Ar was added a solution of /-BuMgCl in THF (0.91 mL, 0.91 mmol). The mixture was cooled to r.t.. diluted with EtOAc and quenched with a sat. NH4CI solution. The mixture was stirred at r.t. for 20 mins and the layers were separated. The aqueous layer was extracted with EtOAc. The organic layers were dried (Na₂SO4), filtered and concentrated under reduced pressure. The crude was purified via silica gel column and further purified via prcp-l ll’l.C to afford 313 as a white solid. LCMS: m/z 549.15 [M+H]⁺.

EXAMPLE 147

Preparation of Compound 314

[0624] Methylmagnesium bromide (27 mL, 3.2 M in THF. 87 mmol) was added to a solution of 314-1 (5.0 g. 29 mmol) in Et₂O (80 mL) at 0 °C. After 1 h of stirring, titanium isopropoxide (8.2 mL, 29 mmol) was added, and the reaction was heated at 50 °C for 2 h. Copious quantities of celite were added to the mixture which was cooled to r.t. The

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PCT/US2014/051642 mixture was basified with 2N NaOH and filtered through celite and washing with CH₂C1₂.

The layers were separated, and the organic layer was concentrated. The mixture was redissolved in CH2CI2 and extracted with IN HC1 (3x). The aqueous extracts were basified with solid K₂CO₃ and back-extracted with EA. The combined organic layers were washed with brine, dried and concentrated to provide crude 314-2 (3.25 g).

[0625] Crude 314-2 (3.28 g, 16 mmol) was dissolved in CH2CI2. Benzyl chloroformate (2.3 mL, 16 mmol) and DIPEA (3.0 mL, 18 mmol) were added, and the reaction was stirred at r.t. for 3 h. The mixture was washed with IN HC1. brine, dried (Na2SO4) and concentrated. The crude was purified via a silica gel chromatography to afford 314-3 as a white solid.

[0626] To a stirring mixture of 314-3 (2 g, 5.9 mmol) in DME (10 mL, deoxygenated prior to using) were added 4.4.6-trimethyl-2-(3,3.3-trifluoroprop-l-en-2-yl)1,3.2-dioxaborinane (1.32 g, 5.9 mmol) and a solution of CS2CO3 (6M, 3 mL). PdCl₂(dppf) (461 mg, 0.59 mmol). The mixture was stirred at 110 °C under microwave reaction conditions for 1 h. The mixture was diluted with EtOAc and water. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel chromatography (EtOAc:hex 0-20%) to afford 314-4 (1.3 g), which was used without further purification.

[0627] To a stirring mixture of 314-4 (1.3 g, 3.2 mmol) in DME (5 mL, deoxygenated prior to using) were added 3-chloro-4-fluorophenylboronic acid (550 mg, 3.2 mmol), a solution of Cs₂CO₃ (6M, 1.5 mL). and PdCl₂(dppf) (230 mg, 0.32 mmol). The mixture was stirred at 110 °C under microwave reaction conditions for 1 h. The mixture was diluted with EtOAc and water. A normal aqueous workup with EtOAc was followed. The crude was purified via a silica gel chromatography (EtOAc:hex 0-20%) to afford 314-5. LCMS: m/z 493.05 [M+H]⁺.

[0628] To a stirring mixture of tert-butyl hydroxycarbamate (2 g, 15 mmol) in THF (10 mL) at 0 °C was added TsCl (2.8 g. 15 mmol) and TEA (2.2 mL. 15.8 mmol). The mixture was stirred at 0 °C for 20 mins, and then warmed to r.t. for 5 mins. The mixture was diluted with DCM and washed with water. A normal aqueous workup with DCM was followed. The crude was purified via a silica gel to afford tert-butyl tosyloxycarbamate as a white solid.

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PCT/US2014/051642 [0629] To a stirring mixture of 314-5 (950 mg. 1.9 mmol) in t-BuOH:water (3:1, 3 mL total volume) at r.t. were added potassium osmate dihydrate (105 mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). The mixture was stirred at r.t. overnight, and then diluted with water and DCM. A normal aqueous work up with DCM was followed. The crude was purified via a silica gel chromatography’ to afford 314-6 (1.3 g, 80% pure). LCMS: m/z 626.20 [M+H]⁺.

[0630] Compound 314-6 was dissolved in a solution of HCI (4N) in dioxane (10 mL) at r.t. The mixture was stirred at r.t. The mixture was concentrated under reduced pressure to afford crude 314-7, which was used without further purification. LCMS: m/z 526.05 [M+H]⁺.

[0631] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid (350 mg. 1.69 mmol) in DMF (1.5 mL) were added HATU (642 mg. 1.69 mmol) and D1PEA (735 mL, 4.2 mmol). The mixture was stirred at r.t. for 10 mins. Compound 314-7 in DML (2 mL) was added, and then stirred for 10 mins. The reaction was quenched with a 10% aqueous solution of NaHCO.3 (10 mL), and then diluted with DCM. A normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 314-8 as a white solid. LCMS: m/z 716.2 [M+H]⁺.

[0632] To a stirring mixture of 314-8 (602 mg, 0.84 mmol) in AcCN (3 mL) at r.t. were added Nal (630 mg, 4.2 mmol) and TMSC1 (453 mg, 4.2 mmol). The mixture was warmed to 60 °C until the starting material disappeared. The mixture was cooled to r.t. and purified by silica gel chromatography (EtOAc:hex 0-50% and then MeOH:DCM 0-20%). The product was further purified via prep-HPLC and then converted to the HCI salt to afford 314. LCMS: m/z 582.2 [M+H]⁺.

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Tabic 3

EXAMPLE 148

Preparation of Compounds 315-317

Example Method	No.	Structure	LCMS: m/z
Compound 314	315	O M l η ^Ηθ P^f3 if η A' · ,-N . X, ...N. J -¾% w/ ci ⁰ '/'NH₂	570.10 [M+H]⁺
Compound 314	316	O h^h°/^cf3 if'^z?f^F ⁰ xj /'NH₂	556.10 [M+H]⁺
Compound 314	317	OH 11 h^hQ/^cf3 r if ⁰	600.15 [M+H]⁺

EXAMPLE 149

Preparation of Compound 318

[0633] To a stirring solution of 318-1 (40 mg, 0.028 mmol) in

EtOAc:EtOH:HOAc (5 mL:1.0 mL:0.1 mL) was added Pd/C (20 mg). The mixture was placed under a IL balloon. The mixture was stirred for several hours until the starting material was consumed. The mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2x10 mL). The mixture was concentrated under reduced pressure and purified viaprep-HPLC to afford 318 as a white solid. LCMS: m/z 548.15 [M+EI]⁺.

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EXAMPLE 150

Preparation of Compounds 319-322

Tabic 4

Example Method	No.	Structure	LCMS: m/z
Compound 318	319	0 o hnVt! h^FAh I X	XY^F ^nh₂	591.15 [M+H]⁺
Compound 318	320	AR /X F ^F\ /^F HO ' Η X ^0H I X	zi.._zF Άγ nh₂	522.15 [M+H]⁺
Compound 318	321	cP Dll hUC OH fY XAnXX/ ⁿ \XA< ^ν<ϊχΧΧ^οι ° LX 'P'nh₂	577.15 [M+H]⁺
Compound 318	322	Ο O h^f3C OH X/'^F ^N XX< ^No XX '/'NHz	599.10 [M+H]^h

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EXAMPLE 151

Preparation of Compound 323 o o

|0634| To a solution of 323-1 (2.5 g. 14.2 mmol) in THF (10 mL) and MeOH (10 mL) was added NaBf L (1.6 g, 42.1 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 mins. The reaction was quenched with 1.0 N HCI and extracted with EtOAc. The combined organic solutions were dried (MgSOj and evaporated under reduced pressure. The residue was purified on a silica gel column (PE:EA 5:1) to give 323-2 as a colorless oil (2.0 g, 79.1%).

[0635] A solution of 323-2 (2.0 g, 11.2 mmol), methyl 4-hydroxy-3methoxybenzoate (2.1 g, 11.5 mmol) and PPhj (4.5 g, 17.3 mmol) was stirred in dry THF (40 mL) at 0 °C under a N₂ atmosphere. DTAD (3.5 g. 17.5 mmol) added dropwise over a period of 5 mins, and the solution was allowed to stir at 50°C for 3 h. After disappearance of the starting material, the solvent was evaporated under reduced pressure. The residue was purified on by column chromatography on silica gel (PE:EA 10:1) to give 323-3 as a white solid (2.8 g. 73.7%): 'H-NMR (CDC1₃, 400 MHz). δ= 7.62-7.60 (dd. J= 1.6 Hz, J= 10.0 Hz, IH), 7.53 (s, IH). 7.34-7.25 (m, 5H), 6.66 (d, J= 8.4 Hz, IH). 4.96-4.93 (m, IH). 4.44 (s. 2H). 4.36-4.32 (m, IH), 3.93 (s. 3H), 3.87 (s. 3H),2.59-2.54 (m, 4H).

[0636] To a mixture of 323-3 (2.8 g, 8.2 mmol) in MeOH (15 mL) was added Pd(OH)₂ on carbon (10%. 500 mg) under N₂. The suspension was degassed under vacuum

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PCT/US2014/051642 and purged with IL (3x). The mixture was stirred under H2 (40 psi) at r.t. for 3 h. The suspension was filtered through a pad of Cclite, and the cake was washed with MeOH. The combined fdtrates were concentrated to give crude 323-4 (1.7 g. 84.5%) which was used without purification.

[0637] To a mixture of 323-4 (1.7 g, 6.7 mmol) in DCM (10 mL) was added DAST (3 mL) at 0 °C. The mixture was stirred at 0 °C for 30 mins. The reaction was quenched by sat. aq. NaHCOj at 0 °C and then extracted with EtOAc. The combined organic layers were washed with brine, dried over iX^SOq and concentrated to dryness. The residue was purified by column chromatography on silica gel (PE:EA 15:1) to give 323-5 as a white solid (800 mg, 47.1%).

10638] A solution of 323-5 (254 mg, 1.0 mmol) and aq. lithium hydroxide (2 N, 1 111L) in THE (5 mL) was stirred at r.t. for 1 h. The mixture was neutralized by using 2N HC1 and extracted with EtOAc. The combined organic solutions were dried (MgSOi). and evaporated under reduced pressure to give 323-6 as a white solid (100 mg. 41.6%).

[0639] Compound 323 was prepared similarly to the preparation of 314. LCMS: m/z 614.15 [M+H]⁺.

EXAMPLE 152

Preparation of Compound 324

[0640] To a stirring mixture of 324-1 (360 mg, 1.73 mmol) and NaF (7.3 mg. 0.173 mmol) in toluene (2 mL) at reflux was added trimethylsilyl-2,2-difluoro-2(fluorosulphonyl)acetate dropwise over 1 h. The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure and loaded into a silica gel column to afford 324-2. LCMS: m/z 259.05 [M+H]⁺.

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PCT/US2014/051642 [0641] To a stirring mixture of 324-2 (320 mg, 1.24 mmol) in THFrwater (1.0 mL:0.2 mL) at r.t. was added aq. LiOI I (155 mg, 3.7 mmol). The mixture was stirred for 2 d.

The mixture was diluted with EtOAc and acidified with 10% aqueous HC1 solution. A normal aqueous work up with EtOAc was followed. Crude 324-3 was used without further purification.

[0642] Compound 324 was prepared similarly to the preparation of 314. LCMS: m/z 618.15 [M+H]⁺.

EXAMPLE 153

Preparation of Compound 325

[0643] To a stirring mixture of 325-1 (0.5 g, 2.75 mmol) in DMF (7 mL) were added CS2CO3 (1.35 g. 4.12 mmol), and 2.2,2-trifluoroethyl 1,1,2.2,3.3,4.4,4nonatluorobutane-1-sulfonate (837 mg, 2.2 mmol). The mixture was heated at 55 °C overnight, and then diluted with EtOAc, and washed with water. The aqueous layer was extracted with EtOAc, dried over Na2SO4. filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 325-2 as a white solid; LCMS: m/z 265.05 [M+H]⁺.

[0644] To a stirring mixture of 325-2 (300 mg. 1.13 mmol) in THF:water (1 mL:0.1 mL) was added aq. LiOH. The mixture was stirred at r.t. overnight. The mixture was diluted with EtOAc and acidified with a IN HC1 aqueous solution. The aqueous layer was extracted with EtOAc, dried over Na2SO4. filtered and concentrated under reduced pressure. Crude 325-3 was used without further purification.

[0645] Compound 325 was prepared similarly to the preparation of 314. LCMS: m/z 624.1 [M+H]⁺.

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EXAMPLE 154

Preparation of Compound 326

[0646] To a stirring mixture of acetic acid (5 mg. 0.083 mmol) in DMF (0.2 mL) were added HAl'U (3.1 mg, 0.083) and DIPEA (17 mg, 0.13 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 326-1 in DMF (0.8 mL) was added, and the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO₃ (10 mL). The mixture was diluted with DCM. and a normal aqueous work up with DCM was followed. Crude product was purified via prep-HPLC to afford 326 as a white solid. LCMS: m/z

624.15 [M+H]⁺.

EXAMPLE 155 Preparation of Compounds 327-329

Table 5

Example Method	Structure	LCMS: m/z
Compound 314	o' y 1 H^c. oh yy y y y ci ⁰ M 327 T nh₂	554.10 [M+H]⁺
Compound 326	Γ II Η^ρ3θ oh yy ° 328 ,% O V H	596.1 [M+H]⁺

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Example Method	Structure	LCMS: m/z
	ο
	a			/.%
	V 7		Η ^Ηθ CF₃
Compound 326			N^X<„N o ,		562.15 [M+H]⁺
			329 A	0
				H

Compound 330			_hf₃coh ·°/ _r ^NJCN 1A_C\|o ...Cao	654.15 [M+H]⁺
			331 γ	-A= H

Compound 306	HO	A	I H \.^OH Π fl	AXA ^νυ^Α>	501.10 [M+H]⁺
		O 333	A_o/
		^o
Compound 314			Ί h^F3^c°H \ζ^ΝΑγΑ	_<;h . , F χΑΑι	559.10 [M+H]⁺
			0	Aa
			334	OMe
	OH	O'”
Compound 334	Λ/τ	ά	fV H \| .OH l· T	573.15 [M+H]⁺
			O 336 G,	F-'q''
	0
Compound 334	..-θΑ'	1	_Fv H b^0H„ΙΨ /C	rv	529.1 [M+H]⁺
		0	337 A-	O'”
	O	^xo
Compound Ο O /1 j j4	Λ. O„ H₂N <		jl H F,C OH [Αΐ” Aⁿ'A_yn_vka_ci	586.05 [M+H]⁺
			O 338	'-/'o''
	Ό
Compound Π Π A	r^N/		H F₃C OH a^N\£A-ⁿ-	/X	550.05 [M+H]⁺
		0	I 339	O'”

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Example Method	Structure	LCMS: m/z
Compound Ο O A J	0 to ^HI\| Τ'θΥπ HF₃C OH i^Y^F Μ ΜγΝ v n xjk_ci0 340	612.1 [M+H J
Compound Ο O A J j4	F 0 ^ρΛ-°Λ h^f3^c _x/°^h i^ii^F ° 341 '-0 I	545.15 [M+H]⁺
Compound 334	o ___,-0 . J . />..,+ i ll HfoC OH \ 0 345 LA_q	609.10 [M+H]⁺
Compound 334	OH O /A/O^± //. F r il η ^ρ3θ oh γ γ ° 346 LX_O	627.15 [M+H]⁺
Compound 334	0 O ^Η2^Ν^ '°ΐ'^Η _H F₃C OH V\+A_r+AA_CI0 347 LA_O	626.15 [M+H]⁺
Compound 334	o to ΗΝ^°Ύ\|1 H^F3°°^H [^V^F V^nJCn ia_ci0 348 k<A₀	652.2 [M+H]⁺
Compound 334	⁰ hn'J' Y\|l hf₃c oh XV ^U ΜγΝΑ N XJk_c\| o 349 to'o-''	598.1 [M+H]⁺

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EXAMPLE 156

Preparation of Compound 330

[0647] To a stirring mixture of 330-1 (20 mg, 0.034 mmol) in DCM (0.4 mL) were added TEA (7 mg, 0.069 mmol) and MsCl (1 drop). The mixture was stirred for 20 mins and slowly warmed to r.t. The mixture was diluted with DCM. and the reaction was quenched with a sat. NaHCCfi solution. The aqueous layer was extracted with DCM. The organic layers were dried (Na₂SO4), filtered and concentrated under reduced pressure. Crude product was purified via prep-HPLC to afford 330 as a white solid. LCMS: m/z 660.10 [M+H]⁺.

EXAMPLE 157

Preparation of Compound 332

[0648] To a stirring mixture of 332-1 (8 mg. 0.014 mmol) in DMF (0.2 mL) was added DMF.DMA (0.2 mL). The mixture was stirred at 90 °C until the starting material was consumed. The crude mixture was concentrated under reduced pressure and used without further purification.

[0649] To a stirring mixture of crude product from the previous step in DCM (0.5 mL) at 0 °C were added hydrazine monohydrate (0.1 mL) and HOAc (0.05 mL). The mixture was warmed to r.t. and then reflux for 30 mins. The mixture was cooled to r.t., and the reaction was quenched with a sat. NaHCCf solution. The aqueous layer was extracted with DCM. dried over Na₂SC>4, filtered and concentrated under reduced product. Crude product was purified via prep-HPLC to afford 332 as a white solid. LCMS: m/z 595.1 [M+H]⁺.

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EXAMPLE 158

Preparation of Compound 342

[0650] To a stirring mixture of 342-1 (50 mg, 0.15 mmol) in t-BuOH:watcr (3:1, 1.3 mL) at 0 °C were added NMO (26 mg. 0.23 mmol) and potassium osmate dehydrate (5.5 mg. 0.016 mmol). The mixture was warmed to r.t. overnight, and then diluted with DCM and water. The aqueous layer was extracted with DCM, dried over Na₂SO4. fdtered and concentrated under reduced pressure. The crude was purified on a silica gel column to afford 342-2 as a brownish oil (50 mg, 91% yield). LCMS: m/z 366.0 [M+H]⁺.

[0651] To a stirring mixture of 342-2 (50 mg. 0.136 mmol) in DCM (1 mL) at 0 °C were added TsCI (52 mg. 0.273 mmol), TEA (60 pL, 0.41 mmol) and DMAP (2 crystals). The mixture was warmed to r.t. for 1 h and then diluted with DCM. The reactino was quenched with sat. NaEICCh solution. The aqueous layer was extracted with DCM, dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 342-3 (65 mg. 92% yield). LCMS: m/z 520.0 [M+H]⁺.

|0652] To a stirring mixture of 342-3 (128 mg. 0.246 mmol) in acetone (1 mL) was added LiBr (64 mg, 0.74 mmol). The mixture was stirred at reflux for 2 h and loaded into a silica gel column to afford 342-4 as a colorless oil (75 mg, 71% yield). LCMS: m/z 427.95 [M+H]⁺.

[0653] To a stirring mixture of 342-4 in DCM (1 mL) at 0 °C was added DAST (58 mL, 0.44 mmol). The mixture was stirred at 0 °C for 30 mins and then warmed to r.t. for

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LCMS: m/z 429.95 [M+H]⁺.

[0654] To a stirring mixture of 342-5 (50 mg. 0.116 mmol) in DMF (2 mL) were added tetrabutyl ammonium azide (330 mg, 1.2 mmol) and tetrabutylammonium iodide (5 mg). The mixture was stirred at 95 °C for 4 h. The mixture was loaded onto a silica gel column, eluting with hexane:EtOAc to afford 342-6 as a colorless oil. LCMS: m/z 393.0 [M+H]⁺.

[0655] To a stirring mixture of 342-6 (25 mg. 0.064 mmol) in I I11:water (10:1. 1.1 mL) was added triphenvlphosphine (polymer-bound, 167 mg, 0.64 mmol). The mixture was stirred at 70 °C for 30 mins, cooled to r.t. and filtered through a plug of celite. The plug was washed several times with EtOAc. The mixture was concentrated under reduced pressure and 342-7 used without further purification. LCMS: m/z 367.0 [M+H]⁺.

[0656] To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid (18 mg, 0.079 mmol) in DMF (0.5 mL) were added HATU (36 mg, 0.095 mmol) and DIPEA (35 pL, 0.191 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 342-7 in DMF (0.5 mL) was added, and the mixture was stirred at for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO₃ (10 mL). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via prepHPLC to afford 342 as a white solid. LCMS: m/z 575.15 [M+H]⁺.

EXAMPLE 159

Preparation of Compound 343 o o

[0657] Compound 343 was prepared according to the method described for 342. LCMS: m/z 574.10 [M+H]⁺.

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EXAMPLE 160

Preparation of Compound 344

[0658] To a stirring mixture of 3-methoxy-4-((4-methoxybenzyl)oxy)benzoic acid (35 mg, 0.095 mmol) in DMF (0.5 mL) were added HATU (45 mg, 0.114 mmol) and DIPEA (35 qL, 0.19 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 344-1 in DMF (0.5 mL) was added, and the mixture was stirred for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCCf (5 mL). The mixture was diluted with DCM and a normal aqueous work up with DCM was followed. The crude was purified via a silica gel column to afford 344-2 as a colorless oil. LCMS: m/z 637.15 [M+H]⁺.

[0659] To a stirring mixture of 344-2 in DCM (1 mL) was added TFA (0.4 mL). The mixture was stirred at r.t. until 344-2 was consumed. The reaction was quenched with a cold sat. NaHCOa solution. The aqueous layer was extracted with DCM. dried over Na^SCfi. filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to give 344-3 as a colorless oil. LCMS: m/z 517.1 [M+H]⁺.

[0660] To a stirring mixture of 344-3 (30 mg, 0.058 mmol) in DCM was added CS2CO3 (47 mg. 0.145 mmol) and 3-bromopyrrolidin-2-one (11.4 mg. 0.07 mmol). The mixture was heated under micro wave irradiation at 70 °C for 1 h. The mixture was filtered through a plug of celite and washed several times with DCM. The mixture was concentrated under reduced pressure and further purified via HPLC to afford 344 as a white solid. LCMS: 111/z 600.15 [M+H]⁺.

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EXAMPLE 161

Preparation of Compound 350

[0661] To a stirring mixture of 350-1 (57 mg, 0.21 mmol) in THF (1 mL) at 0 °C was added NaH (17 mg. 0.43 mmol). The mixture was stirred at 0 °C for 5 mins, and then methyl iodide (61 mg. 0.43 mmol) was added. The mixture was warmed to r.t. and then diluted with EtOAc. The reaction was quenched with a sat. NH4CI solution. The aqueous layer was extracted with EtOAc. dried over Na?SO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to give 350-2. LCMS: m/z 280.05 [M+H]'.

[0662] To a stirring mixture of 350-2 (50 mg. 0.17 mmol) in THF:MeOH:water (1:0.4:0.1) at r.t. was added aq. TiOH (36 mg, 0.86 mmol). The mixture was stirred overnight at r.t. The mixture was diluted with EtOAc and acidified with a IN HC1 solution. The aqueous layer was extracted with EtOAc, dried over Na2SO4, filtered and concentrated under reduced pressure. Crude 350-3 was used without further purification. LCMS: m/z 266.05 [M+H]⁺.

[0663] Compound 350 was prepared similarly according to the methods for 349. LCMS: m/z 612.1 [M+H]⁺.

EXAMPLE 162

Preparation of Compound 351

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PCT/US2014/051642 [0664] To a stirring mixture of 351-1 (15 mg, 0.0295 mmol) in DCM (1 mL) at 0 °C were added acetic anhydride (10 mg, 0.09 mmol), TEA (20 μΐ) and DMAP (1 crystal). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a sat. NaHCOs (5 mL). The aqueous layer was extracted with EtOAc, dried over Na₇SO4, filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 352 as a white solid. LCMS: m/z 549.10 [M+H]⁺.

EXAMPLE 163

Preparation of Compound 352

[0665] To a stirring mixture of 352-1 (25 mg, 0.047 mmol) in DMF (0.1 mL) was added DMF. DMA (0.1 mL). The mixture was stirred at 60 °C until the starting material was consumed. The mixture was cooled to r.t. and concentrated under reduced pressure. The crude used was without further purification. To the stirring crude in DCM at 0 °C were added HOAc (3 drops) and methyl hydrazine (3 drops). The mixture was warmed to r.t. for 20 mins and heated to reflux. The mixture was cooled to r.t., diluted with DCM and quenched with a cold sat. NaIICO.3 solution. The aqueous layer was extracted with DCM (3 x 10 mL). dried over Na?SO4, filtered and concentrated under reduced pressure. The crude was purified via prep-HPLC to afford 352 as a white solid. LCMS: m/z 582.15 [M+H]⁺.

EXAMPLE 164

Preparation of Compound 353

[0666] To a solution of 353-1 (53 mg, 0.11 mmol) in TIIF (4 mL) was added

McMgCl (1 mL). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with a sat. NH4CI solution. The organic layers was washed with brine, dried over Na₂SO₄ and

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PCT/US2014/051642 concentrated. The crude was purified by prep-HPLC to give 353 (20 mg, 40%) as a white solid. LCMS: m/z 469.3 [M+II]⁺.

EXAMPLE 165

Preparation of Compound 354 ci

354-2 354-3 354-4 354-5

[0667] A solution of i-PrMgCl (2.75 mL, 3.84 mmol) in THF was added dropwise to a stirring mixture of 354-1 (1 g, 3.66 mmol) at -45 °C over 5 mins. The mixture was stirred for 1 h, and then cyclobutanone (256 mg, 3.66 mmol) in THF (1 mL) was added. The mixture was warmed to r.t. and stirred overnight. The mixture was diluted with EtOAc, and the reaction quenched with a sat. NH4CI solution. The aqueous layer was extracted with EtOAc. dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 354-2 as a colorless oil. LCMS: m/z 218 [M+H]⁺.

[0668] To a stirring mixture of 354-2 (0.4 g, 1.83) in CH₃CN (4 mL) at 0 °C was added dropwise H2SO4 (cone.) (490 pL, 9.2 mmol) over 5 mins. The mixture was warmed to r.t. for 1 h and then warmed to 80 °C for 30 mins. The mixture was cooled to r.t.. and then diluted with EtOAc. The reaction was quenched with a sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc. dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 354-3 as a white solid. LCMS: m/z 258.95 [M+H]⁺.

[0669] Steps 3-6 were conducted in a similar manner as 314 to provide 354. LCMS: m/z 636.15 [M+H]⁺.

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EXAMPLE 166

Preparation of Compound 355

[0670] To a stirring mixture of 354 (16 mg. 0.025 mmol) in 4N HC1 in dioxane (2 mL) was added a 6N HC1 aqueous solution. The mixture was heated under microwave irradiation at 120 °C for 1 h. The mixture was cooled to r.t., diluted with DCM and neutralized with a cold sat. Nal ICCL solution. The aqueous layer was extracted with DCM, dried over Na₂SO4 and concentrated under reduced pressure. The crude was purified via prep-IIPLC to afford 355 as a white solid. LCMS: m/z 594.10 [M+H] \

EXAMPLE 167

Preparation of Compound 356

356-1 356-2 356-3

O

[0671] To a stirring mixture of 356-1 (0.3 g, 1 mmol) in DMF at r.t. were added Cs₂CO₃ (488 mg, 1.5 mmol), Nal (15 mg) and 1-bromo-2-fluorocthanc (127 mg, 1 mmol). The mixture was heated to 45 °C overnight. The mixture was diluted with EtOAc and quenched with water. The aqueous layer was extracted with EtOAc. dried over Na₂SO4 and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 356-2. LCMS: m/z 345.1 [M+H]⁺.

[0672] Compound 356 was prepared in 4 steps using the similar methods as 314. LCMS: m/z 628.15 [M+H]⁺.

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EXAMPLE 168

Preparation of Compounds 357-361 and 363

Tabic 6

Example Method	Structure	LCMS: m/z
Compound 327	OH 7 _{c r} /^^F f\| \| h ^f3^c OH \| Ϊ M-yNjV N 11_C\| ⁰ 357 ΉΗ₂	572.15 [M+H]⁺
Compound 334	Ν' ^F\ Azk /< /^F t ii h^h°p^f3 rY ^N ΥΥ ^N i O 358 LY/θ	591.10 [M+H]⁺
Compound 306	Ό °yS hA °^h rt^F ° 359 YY_Q 1	501.10 [M+H]⁺
Compound 352	AN 0 ^NN/^F/^O Y/: <1 η YY ^h v^OH ΓΥ O 360 YYq 1	568.15 [M+H]⁺
Compound 327	O' _..·Ο ,/ . ,3> / ^F X 1 H^H°P^F3 \ Y /^f/ⁿYaY/ ⁰ 361 A> Υη₂	520.15 [M+H]⁺
Compound 383	o' ^F\___;,.o j H₂N / ,F ^F Y 11 H Loh ί\| η ΥΥγ ^N ΥΥ A^Y\_C\| O 363 YY_Q/	553.10 [M+H]⁺

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EXAMPLE 169

Preparation of Compound 362

O 0

[0673] To a stirring mixture of 336 (20 mg, 0.035 mmol) in DCM (1 mL) at r.t. was added Dess-Martin periodinane (150 mg, 0.175 mmol). The mixture was stirred at r.t. for 1 h and then quenched with 5% NaHSOs and a sat. NaHCO.3 solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried (Na^SCfi), filtered and concentrated under reduced pressure. The crude was purified via HPLC to afford 362 as a white solid. LCMS: m/z 571.1 [M+H]⁺.

EXAMPLE 170

Preparation of Compound 364

[0674] Methylmagnesium bromide (1.4 M in THE, 0.30 mL, 0.68 mmol) was added to a solution of bromoketone (0.163g, 0.45 mmol) in THF (2 mL) at 0 °C. After 30 mins, the reaction was quenched with NH4CI and extracted with EA, dried over anhydrous Na^SCfi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-2 (0.115 g, 68%). LCMS: m/z 375.95 [M+H]¹.

[0675] To a solution of 364-2 (0.115 g, 0.31 mmol) in CH?CL (3 mL) at 0 °C was added DAST (81uL. 0.61 mmol). The solution was stirred for 1 h. The mixture was diluted with sat. NaHCOs and extracted with EA. The combined organic phase was dried over

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PCT/US2014/051642 anhydrous Na₂SO₄ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-3 (0.071 g, 61%). LCMS: m/z 377.95 [M+I I]⁺.

[0676] To a solution of 364-3 (0.071 g, 0.19 mmol) in DMF (1 mL) was added tetrabutylammonium azide (0.7 g, 0.94 mmol). The solution was stirred for 3 h at 90 °C and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 364-4 (0.054 g. 84%). LCMS: m/z 339.05 [M+H]⁺.

[0677] To a solution of 364-4 (0.054 g. 0.16 mmol) in THF (1 mL) and water (1 drop) was added polymer supported triphenylphosphine (0.5 g, 1.5 mmol). The solution was stirred for 2 h at 60 °C. The mixture was diluted with EA and filtered to remove resin. The organic phase was washed with brine, dried over anhydrous Na₂SO_t and concentrated to provide crude 364-5 (0.032g. 63%), which was used without further purification. LCMS: m/z 313.00 [M+H]⁺.

[0678] Diisopropylethylamine (52 uL. 0.31 mmol) was added to a solution of 4(2-fluoroethoxy)-3-methoxybenzoic acid (33 mg, 0.15 mmol). 364-5 (32 mg, 0.10 mmol) HBTU (62 mg. 0.16 mmol) in DMF (1 mL). The solution was stirred at r.t. for 3 h. The mixture was diluted with EtOAc, and washed with IN HCI, sat. Na₂CO₃ and brine, dried over MgSO₄ and concentrated under reduced pressure. The crude was purified by reverse phase IIPLC to give 364 (10.4 mg. 20%). LCMS: m/z 509.05 [M+I I]⁺.

EXAMPLE 171

Preparation of Compound 365

[0679] Diisopropylethylamine (0.13mL, 0.75 mmol) was added to a solution of 3methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid (33 mg. 0.15 mmol). 365-1 (78

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PCT/US2014/051642 mg, 0.25 mmol) HATH (0.15 g, 0.40 mmol) in DMF (1 mL). The solution was stirred at r.t.

for 3 h. The mixture was diluted with EtOAc, and washed with IN HC1, sat. Na₂CO3 and brine, dried over MgSCfi and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (EA:hexane) to give 365-2. LCMS: m/z 627.20 [M+H]⁺.

[0680] Compound 365-2 was deprotected using TFA (0.25 mL) in CH₂C1₂ (1.0 mL) at r.t. for 8 mins. The reaction was quenched with cold NaHCOi and extracted with CH₂C1₂. The crude was purified by reverse phase HPLC to give 365 (10.4 mg, 8%). LCMS: m/z 507.01 [M+H]⁺.

EXAMPLE 172

Preparation of Compound 368

[0681] Compound 368-1 (5.0 g, 39 mmol) and solid NaHCCf (5.0 g. 60 mmol) were suspended in water (40 mL) and heated to 90 °C. Formaldehyde (10 mL) was added portionwise over 8 h and the reaction was heated at 90 °C overnight. The mixture was cooled to 0 °C and acidified to pH 1 with 6N HC1. The solution was stirred at 0 ^UC for 1 h. The reaction was filtered, and the filtrate extracted with EA to provide 368-2 (4.9 g, 79%). 'H NMR (400 MHz, CDC1₃): δ 7.21 (d. J = 4.6. 1H), 7.20 (d, J = 4.6, 1H), 4.4 (s, 2H).

[0682] lodomethane (4.5 mL, 72 mmol) was added to a solution of 368-2 (7.7 g, 48 mmol) and potassium carbonate (13 g, 144 mmol) in DMF (60 mL). The mixture was stirred at 50 °C for 1 h. The mixture was diluted with EA, washed with brine, dried over anhydrous Na₂SC>4 and concentrated. The residue was purified by chromatography on silica

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PCT/US2014/051642 gel (EArhexane) to give 368-3 (2.57 g, 31%). 'H NMR (400 MHz, CDC1₃): δ 7.20 (s, 2H), 4.6 (d, J = 6.0, 2H).

[0683] Methanesulfonyl chloride (1.4 mL. 0.18 mmol) was added to a solution of 368-3 (2.57 g, 15 mmol) and diisopropylethyl amine (3.9 mL, 22 mmol) in CILCL (30 mL) at 0 C. After 30 mins, the mixture was diluted with CH₂C1₂. washed with IN HC1 and brine, dried over anhydrous Na₂SO4 and concentrated. The residue was dissolved in DMF (10 mL) and treated with sodium cyanide (2.2 g. 44 mmol) at 80 °C for 3 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na₂SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-4 (1.13 g, 41%). LCMS: m/z 183.03 [M+H]⁺.

[0684] Pd(dppf)Cl₂ (0.45 g, 0.61 mmol) was added to a solution of 368-4 (0.56g. 3.1mmol). 3-chloro-4-fluorophenyl boronic acid (0.80g, 4.6 mmol) in CH₃CN (10 mL) and IM K₂CO₃ (5 mL). The reaction vessel was heated under micro wave irradiation for 3 h at 120 °C. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na₂SO| and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-5 (0.70 g, 81%). LCMS: m/z 277.05 [M+H]⁺.

[0685] Sodium hydride (76 mg, 1.9 mmol) was added to a solution of 368-5 (0.21 g. 0.76 mmol) in DMF (1 mL). After 5 mins, iodomethane (0.14 mL. 2.3 mmol) was added, and the mixture was stirred for 30 mins. The reaction was quenched with NII4CI. diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 368-6 (0.19 g, 81%). LCMS: m/z 305.00 [M+H]⁺.

[0686] Lithium aluminum hydride (1.8 mL, IM in THF. 1.8 mmol) was added to a solution of 368-6 (0.19 g. 0.61 mmol) in THF (5 mL), and the mixture was stirred at r.t. for 2 h. The reaction was quenched by the addition of solid sodium sulfate decahydrate and stirred for 10 mins. The solids were fdtered, and the filtrate was concentrated to yield 368-7 (0.16 g, 85%). LCMS: m/z 309.05 [M+H]⁺.

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PCT/US2014/051642 [0687] Compounds 368-8 and 368 were prepared in the same manner as 365.

Compound 368-8: LCMS: m/z 624.3 [M+H]⁺. Compound 368: LCMS: m/z 503.15 [M+H]⁺.

EXAMPLE 173

Preparation of Compound 369

[0688] Methyl vanillate (0.25g, 1.4 mmol) and vinyl acetate (0.25 mL, 2.7 mmol) were added to [IrCl(cod)]2 (9 mg. 0.014) and sodium carbonate (52 mg. 0.49 mmol) in toluene (1 mL). The mixture was flushed with Ar and stirred at 110 °C for 1.5 h and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 369-1 (0.159 g, 55%). 'H NMR (400 MHz, CDC1₃): δ 7.61 (dd. J = 1.6. 8.0. IH), 7.0 (d. J = 8.4, IH), 6.63 (dd. J = 6.0, 14. IH), 4.87 (dd, J - 2.4. 14, IH). 4.55 (dd, J - 2.0, 6.0. IH), 2.92 (s. 2H), 3.91 (s, 3H).

[0689] Diethylzinc (9 mL, 9.0 mmol) was added dropwise to a solution of 369-1 (0.234 g, 1.1 mmol) and diiodoethane (0.72 mL, 9.0 mmol) in dichloroethane (3 mL) at 0 °C. The mixture was stirred at r.t. overnight, and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NirSOi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 369-2 (0.121 g. 55%). 'H NMR (400 MHz, CDCL): δ 7.61 (dd. J = 1.6. 8.0, IH). 7.0 (d. J = 8.4, IH), 6.63 (dd. J = 6.0, 14, IH), 4.87 (dd, J = 2.4, 14, IH). 4.55 (dd, J = 2.0, 6.0, IH), 3.92 (s. 3H).

[0690] 2N Sodium hydroxide (1 mL) was added to a solution of 369-2 (58 mg) in methanol (3 mL), and the mixture was stirred at r.t. overnight. The mixture was acidified with IN HC1 and extracted with EA to give 369-3 (50 mg, 86%). 'H NMR (400 MHz,

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CDC1₃): δ 7.78 (d, J = 1.95, IH), 7.58 (s, IH), 7.30 (d, J = 1.95, IH), 3.91 (s, 3H), 3.80-3.83 (m. 1H), 0.85-0.89 (m, 4H).

[0691] Compound 369 was prepared in a similar manner as 364. LCMS: m/z 501.1 [M+H]⁺.

EXAMPLE 174

Preparation of Compound 371

[0692] Isobutylene (10 mL, 105 mmol) was added to a solution of methyl vanillate (1 g, 5.5 mmol) and H2SO4 (3 drops) in CHiCL (15 mL) in a sealed vessel at -40 °C. The mixture was warmed to r.t. and stirred over 2-3 d. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 371-2 (0.161 g, 12%). 'H NMR (400 MHz, CDC1₃): δ 7.71 (d, J = 6.26, IH), 7.63 (d, J = 1.96, IH), 7.09 (d, .1 = 8.26, IH), 3.88 (s. 3H), 3.87 (s. 3H). 1.41 (s, 9H).

[0693] Compound 371 prepared in a similar manner as 364. LCMS: m/z 517.2 [M+H]⁺.

EXAMPLE 175

Preparation of Compound 372

[0694] Potassium fluoride (0.10 g, 1.7 mmol) and methyl vanillate (0.31 g, 1.7 mmol) were mixed in methanol (5 mL) for 15 mins. The mixture was concentrated, coevaporating with diethyl ether (2x). The residue was dissolved in DMSO (2.0 mL) and added to difluoroiodoethane (0.36 g, 1.9 mmol) in a vial. The vial was flushed with Ar, sealed, and heated at 120 °C overnight. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na2SO4 and concentrated. The residue

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PCT/US2014/051642 was purified by chromatography on silica gel (EA:hexane) to give 372-1 (0.060 g. 14%). 'H

NMR (400 MHz. CDCfi): δ 766 (dd, .1 = 1.95, 8.41, 1H). 7.59 (d, J = 1.95, 1H), 6.92 (d, .1 =

8.41, 1H), 6.00-6.30 (m, 1H), 4.24-4.31 (m, 2H), 3.91 (s, 3H). 3.91 (s, 3H).

[0695] Compound 372 was prepared in a similar manner as 364. LCMS: m/z 525.10 [M+H]⁺.

EXAMPLE 176

Preparation of Compound 374

[0696] Sodium iodide (1 mg) was added to a solution of methyl vanillate (0.26 g. 1.4 mmol), bromocy clobutane (0.40 mL, 4.3 mmol), potassium carbonate (0.98 g. 4.3 mmol) in NMP (1.5 mL). The mixture was heated under microwave irradiation at 180 °C for 1.5 h and then diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NhoSOi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 374-1 (0.18 g, 54%). 'H NMR (400 MHz, CDC1₃): δ 7.3 (d. J 8.41, 1H), 7.53 (s. 1H), 6.74 (d, J = 8.41. 1H), 4.4-4.7 (m, 1H), 3.92 (s. 3H), 3.89 (s. 3H).

[0697] Compound 372-2 was hydrolyzed in a similar manner as 369, and 372 was prepared in a similar manner as 364. LCMS: m/z 568.9 [M+H]⁺.

EXAMPLE 177

Preparation of Compound 375

[0698] Tetrabutylammonium azide (0.33 g, 0.57 mmol) was added to 375-1 (60 mg, 0.16 mmol) in DMF (1 mL), and the mixture was heated at 80 °C for 5h. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over

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PCT/US2014/051642 anhydrous Na^SCfi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 375-2 (0.052 g, 96%). LCMS: m/z 337.05 [M+I I]⁺.

[0699] NaH (12 mg, 0.31 mmol) was added to 375-2 (52 mg, 0.15 mmol) in DMF (1 mL). The mixture was stirred at r.t. for 15 mins, lodomethane (30 uL. 0.46 mmol) was added, and the mixture reaction was stirred for 2 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 375-3 (0.052 g, 98%). LCMS: m/z 351.05 [M+Hf.

[0700] Compound 375 was prepared in a similar manner as 364. ECMS: m/z 539.15 [M+H]⁺.

EXAMPLE 178

Preparation of Compound 377

[0701] Pd(dppf)Cl₂ (20 mg. 0.02 mmol) was added to a solution of 2,6-dichloro3-fluoropyridine (0.20 g, 0.78 mmol) and 1 -(trifluoromethyl)vinylboronic acid hexylene glycol ester (0.18 g, 0.86 mmol) in CH₃CN (0.5 mL) and IM K₂CO₃ (0.25 mL). The mixture was heated under micro wave irradiation for 1 h at 110 °C. The reaction was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na₂SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 377-1 (0.10 g, 47%). LCMS: m/z 271.90 [M+H]⁺.

[0702] Pd(dppf)Cl₂ (75 mg. 0.091 mmol) was added to 377-1 (0.493 g. 1.8 mmol) and 3-chloro-4-fluorophenyl boronic acid (0.38 g, 2.7 mmol) in CH3CN (2 mL) and IM K₂CO₃ (0.5 mL). The mixture was heated under microwave irradiation at 110 °C for 30 mins. The mixture was heated under microwave irradiation for 1 h at 110 °C. The mixture was diluted with EA. and the organic phase was washed with water and brine, dried over

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PCT/US2014/051642 anhydrous NaiSCh and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 377-2 (0.286 g, 33%). LCMS: m/z 319.95 [M+II]⁺.

[0703] Potassium osmate (50 mg, 0.13 mmol) was added to a suspension of 377-2 (0.286g, 0.89 mmol) and tert-butyl (tosyloxy)carbamate (0.36 g. 1.3 mmol) in t-butanol (2 mL) and water (0.6 mL), and the mixture was stirred overnight at r.t. The crude was poured directly onto a silica gel column and chromatographed (EA:hexane) to give 377-3. (0.162 g. 40%). TCMS: m/z 398.83 [M+H]⁺.

[0704] 4N HC1 in dioxane (2 mL) was added to 377-3 (0.16 g), and the mixture was stirred at r.t. for 1 h. The mixture was concentrated to give 377-4, which was used without further purification. Compound 377 was prepared in a similar manner as 364. LCMS: m/z 506.20 [M+H]⁺.

EXAMPLE 179

[0705] NaH (0.13 g. 3.1 mmol) was added to a solution of methyl vanillate (0.44 g, 2.4 mmol) and 2-iodopropane (1.2 mL. 12 mmol) in DMF (3.0 mL). and the mixture was heated at 65 °C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 378-1 (0.50 g, 93%). 'H NMR (400 MHz. CDCLfi: δ 7.65 (dd, J = 1.95. 8.6, IH), 7.55 (d, J = 1.96. IH). 6.90 (d, J = 8.6. IH). 4.61-4.66 (111, IH), 3.91 (s. 3H), 3.58 (s. 3H). 1.41 (s, 3H). 1.39 (s, 3H).

[0706] Compound 378-1 was hydrolyzed in a similar manner as 369 to give 3782. 'H NMR (400 MHz, CDCI3): δ 7.74 (dd, J = 1.95, 8.6, IH), 7.60 (d, J = 1.96, IH), 6.92 (d, J = 8.6. IH), 4.65-4.68 (m, IH), 3.92 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H). Compound 378 was prepared in a similar manner as 364. LCMS: m/z 557.10 [M+H]⁺.

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EXAMPLE 180

Preparation of Compound 379

[0707] NaH (0.13 g. 3.1 mmol) was added to a solution of methyl vanillate (0.44 g, 2.4 mmol) and chloromethylmethyl sulfide (0.24 mL. 2.8 mmol) in DMF (3.0 mL), and the mixture was stirred for 1 h. The mixture w^ras diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous NIvSOi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 379-1 (0.57 g, 92%).

[0708] MCPBA (0.9 g, 5.2 mmol) was added to 379-1 (0.576 g, 2.4 mmol) in CEEC1? (3 mL), and the mixture was stirred at r.t. for 1 h. The mixture was washed with Na/CO;. dried over anhydrous NaoSCfi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 379-2 (0.40 g. 70%).

[0709] Compound 379-2 was hydrolyzed in a similar manner as 369 to give 3793. Compound 379 was prepared in a similar manner as 364. LCMS: m/z 553.10 [M+I I] \

EXAMPLE 181

Preparation of Compound 380

[0710] 2 -Bromoacetamide (0.46 g, 3.4 mmol) was added to methyl 3-fluoro-4hydroxybenzoate (0.29 g, 1.7 mmol) and potassium carbonate (0.70 g, 5.0 mmol) in DMF (1 mL), and the mixture was heated to 65 ^UC for lh. The mixture was diluted with EA. and the organic phase was washed with water and brine, dried over anhydrous Na/SCfi and concentrated. Compound 380-1 was crystallized from EA and collected by filtration (0.27 g,

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71%). 'H NMR (400 MHz, dmso-i/₆): δ 7.67-7.42 (m, 2H), 7.50 (br. s, IH), 7.38 (br. s, IH), 7.11 (t, J = 8.62, 1H), 4.62 (s, 2H), 3.79 (s, 3H).

[0711] Compound 380-1 was hydrolyzed in a similar manner as 369 to give 3802. 'H NMR (400 MHz, dmso-J₆): δ 7.63-7.69 (m, 2H). 7.49 (br. s, IH), 7.38 (br. s, IH), 7.08-7.11 (m, 1H). 4.61 (s, 2H). Compound 380 was prepared in a similar manner as 364. LCMS: m/z 560.05 [M+H]⁽.

EXAMPLE 182

Preparation of Compound 381

HO.

[0712] 2 -Bromoacetamide (0.46 g. 3.4 mmol) was added to methyl 3-bromo-4hydroxybenzoate (0.46 g, 1.7 mmol) and potassium carbonate (0.70 g, 5.0 mmol) in DMF (1 mL), and the mixture was heated to 65 °C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous NajSCfi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give

381-1 (0.091 g. 24%). 'H NMR (400 MHz, dmso-i/₆): δ 7.95 (d, J = 2.34, IH), 7.90 (dd, J =

2.34, 8.61, IH), 7.45 (br. s, IH), 7.34 (br. s, IH). 7.06 (d, J = 8.61, IH), 4.65 (s. 2H), 3.78 (s,

3H).

[0713] 381-1 was hydrolyzed in a similar manner as 369-2 to give 381-2. 'll

NMR (400 MHz, dmso-J₆): δ 8.12 (d, J = 2.34, III), 7.87 (dd, J = 2.35, 6.0, III), 7.15 (d, J = 6.0, IH), 4.87 (s, 2H).

[0714] Compound 381 was prepared in a similar manner as 364. LCMS: m/z 621.76 [M+H]⁺.

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EXAMPLE 183

Preparation of Compound 382 o

[0715] Diisopropylethylamine (0.15 mL. 0.84 mmol) was added to a solution of 382-1 (0.10 g, 0.34 mmol), 3-methoxy-4-(2-((methosybenzyl)oxy)ethoxy)benzoic acid (0.15 g, 0.51 mmol) and HATU (0.25 g, 0.67 mmol) in DMF (1 mL). The mixture was stirred at r.t. for 2 h. The mixture was diluted with EA. and the organic phase was washed with water and brine, dried over anhydrous Na^SCL and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 382-2 (0.15 g. 76%). LCMS: m/z 581.15 [M+H]⁺.

[0716] Compound 382-2 was deprotected in a similar manner as 368 to give 3823 LCMS: m/z 461.10 [M+H]⁺.

[0717] Cesium carbonate (0.11 g, 0.33 mmol) was added to a solution of 382-3 (0.050 g, 0.11 mmol) and 2-(Boc-amino)ethyl bromide (0.048 g. 0.22 mmol) in DMF (1 mL). The mixture was heated under microwave irradiation at 70 °C for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na2SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 382-4 (39 mg, 60%). LCMS: m/z 604.20 [M+H]⁺.

[0718] Hydrochloric acid in dioxane (1.5 mL, 4N) was added to 382-4 (39 mg, 0.077 mmol). The mixture was stirred at r.t. for 1 h and then concentrated under reduced

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PCT/US2014/051642 pressure. The crude was purified by reverse phase HPLC to give 382 (8 mg, 25%). LCMS: m/z 503.95 [M+II]⁺.

EXAMPLE 184

Preparation of Compound 383

[0719] Compound 383-1 was prepared in a similar manner as 364 to give 383-2. LCMS: m/z 487.10 [M+H]⁺.

[0720] Dess-Martin periodinane (0.58 g, 1.4 mmol) was added to 383-2 (0.337 g, 0.69 mmol) in CH₂C1₂ (10 mL). and the mixture was stirred at r.t. for 1 h. The mixture was diluted with CH₂C1₂, washed with Na₂CO; and brine, dried over anhydrous Na₂S()| and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to provide 383-3 (0.144 g, 43%). LCMS: m/z 485.10 [M+H]⁺.

[0721] Potassium tert-butoxide (40 mg, 0.36 mmol) was added to trimethylsulfoxonium iodide (65 mg, 0.30 mmol) in DMSO (1 mL). and the mixture was stirred at r.t. for 30 mins. Compound 383-3 (0.144 g, 0.30 mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 383-4 (0.050 g. 33%). LCMS: m/z 499.15 [M+H]⁺.

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PCT/US2014/051642 [0722] Compound 383-4 (0.050 g, 0.10 mmol) was dissolved in 6N HCI (1 mL) and MeOH (1 mL) and heated at 60 °C for 2 h. The mixture was concentrated, and the crude was purified by reverse phase HPLC to give 383 (14 mg, 28%). LCMS: m/z 517.10 [M+H]⁺.

EXAMPLE 185

Preparation of Compound 384

[0723] Potassium tert-butoxide (81 mg. 0.72 mmol) was added to trimethylsulfoxonium iodide (0.13 g, 0.60 mmol) in DMSO (1 mL), and the mixture was stirred at r.t. for 30 mins. Compound 384-1 (0.329 g. 0.60 mmol) in DMSO (0.5 mL) was added, and the mixture was stirred for 1 h. The mixture was diluted with EA, and the organic phase was washed with water and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 384-2 (0.11 g, 37%). LCMS: m/z 499.15 [M+H]⁺.

[0724] Compound 384-2 (0.11 g. 0.22 mmol) was dissolved in 6N HCI (1 mL) and MeOH (1 mL) and heated at 60 °C lor 2 h. The mixture was concentrated and treated with 2N NaOH (2 mL) in MeOH (2 mL) for 2 h. The crude was purified by reverse phase IIPLC to give 384 (17 mg, 5%). LCMS: m/z 517.10 [M+H]⁺.

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EXAMPLE 186

Preparation of Compound 385

[0725] LDA (2 M in THF, 1.4 mL. 2.8 mmol) was added dropwise to a solution of 385-1 (0.93 g, 2.5 mmol) in THF (10 mL) at -78 °C, and the mixture was stirred at -78 °C for 15 mins. N-fluorobenzenesulfonimide (1.2 g, 3.8 mmol) was added, and the mixture was stirred for 3 h. The mixture was warmed to r.t.. and the reaction was quenched with IN HCl. The mixture was extracted with EA. and the organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 385-2 (0.57 g, 59%). LCMS: m/z 386.10 [M+H]⁺.

[0726] Sodium borohydride (0.12 g, 3.1 mmol) was added to a solution of 385-2 (0.14 g, 0.36 mmol) in EtOH. The mixture was stirred at r.t. for 2 h. The reaction was quenched with IN HCl and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 385-3 (0.040 g, 33%). LCMS: m/z 330.00 [M+H]⁺.

[0727] Compound 385-3 (25 mg, 0.076 mmol) in THF (1 mL) was added to NaH (3.0 mg, 0.076 mmol) in THF (0.5 mL), and the mixture solution was stirred for 30 mins. TBDMSC1 (11 mg. 0.076 mmol) was added, and the mixture w^ras stirred at r.t. for 2 h. The reaction was quenched with IN HCl and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The residue was purified by

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PCT/US2014/051642 chromatography on silica gel (EA:hexane) to give 385-4 (0.014 g, 41%). LCMS: m/z 444.10 [M+I I]⁺.

[0728] Triflic anhydride (45 uL, 0.27 mmol) was added to a solution of 385-4 (60 mg. 0.14 mmol) and 2,6-lutidine (47 uL. 0.40 mmol) in CHnCl? (1 mL) at -78 °C. The mixture was warmed to r.t. The reaction was quenched withlN HC1 and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude triflate was immediately dissolved in NMP (0. 5 mL) and tetrabutylammonium azide (0.39 g. 1.4 mmol) was added, and the mixture was heated at 65 °C for 1 h. The mixture was diluted with EA, and organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to give 385-5 (0.057 g, 114%). LCMS: m/z 355.05 [M+H]⁺.

[0729] Compound 385-5 was reduced in a similar manner as 364 to give 385-6. LC/MS: [M+H] 329.00. Diisopropylethylamine (62 uL, 0.36 mmol) was added to a solution of 385-6 (54 mg, 0.12 mmol), 4-cyclopropoxv-3-methoxybenzoic acid (37 mg, 0.18 mmol) and HBTU (81 mg, 0.21 mmol) in DMF (1 mL), and the mixture was stirred at r.t. for 1 h. The mixture was diluted with EA and washed with 1 N HCL sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated. The crude was purified by reverse phase HPLC to give 385 (14 mg, 22%). LCMS: m/z 520.15 [M+FI]⁺.

EXAMPLE 187

Preparation of Compound 386

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PCT/US2014/051642 [0730] Methyl magnesium bromide (1.4 M in THF, 6.0 mL, 8.4 mmol) was added to a solution of ethyl 2,6-dichloroisonicotinate (0.74 g, 3.4 mmol) in THF (20 mL) at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with IN HC1 and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexane) to give 386-2 (0.63 g. 88%). LCMS: m/z 206.00 [M+H]⁺.

[0731] TBDMSOTf (2.6 mL. 12 mmol) was added dropwise to a solution of 3862 (0.80 g. 3.9 mmol) and 2,6-lutidine (2.3 mL, 19 mmol) in CH2CI2 (20 mL). and the mixture was stirred at r.t. for 3 h. The reaction was quenched with IN HCI and extracted with EA. The organic extracts were washed with brine, dried over sodium sulfate and concentrated. The crude was purified by chromatography on silica gel (EA:hexaiie) to give 386-3 (1.2 g. 96%). LCMS: m/z 320.05 [M+H]⁺.

[0732] Compounds 386-4, 386-5, 386-6. 386-7 and 386-8 were prepared in a similar manner as 377. 386-4: LCMS: m/z 350.10 [M+H]⁺. 386-5: LCMS: m/z 474.15 [M+H]⁺. 386-6: LCMS: m/z 607.20 [M+H]⁺. 386-7: LCMS: m/z 507.15 [M+H]⁺. 386-8: LCMS: m/z 697.25 [M+H]⁺.

[0733] TBAF (IM in THF, 0.13 mL, 0.13 mmol) was added to a solution of 386-8 (25, mg, 0.043 mmol), and the mixture was stirred at r.t. for 1 h. The mixture was concentrated, and 386 was purified by reverse phase HPLC (5 mg, 20%). LCMS: m/z 583.20 [M+H]⁺.

EXAMPLE 188

Preparation of Compound 387

Cl [0734] Compound 314 (10 mg. 0.021 mmol) was dissolved in CHiCL (1 mL). Ethyl isocyanate (10 uL, 0.12 mmol) was added, and the mixture was stirred at r.t. lor 5 h. The reaction was quenched with methanol (2 mL) and concentrated. Compound 314 was purified by HPLC (4.1 mg, 40%). LCMS: m/z 653.20 [M+H]⁺.

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EXAMPLE 189

Preparation of Compound 388

[0735] Sodium triacetoxyborohydride (48 mg. 0.23 mmol) was added to a solution of 318 (28 mg. 0.051 mmol) and acetaldehyde (9 uL. 0.16 mmol) in CH2CI2 (1 mL).

Additional acetaldehyde and reducing agent were added every 30 mins for 5 h. The reaction was quenched with ammonium chloride and extracted with CH2CI2. Compound 388 was purified by reverse phase HPLC (14 mg. 50%) LCMS: m/z 576.20 [M+H]⁺.

EXAMPLE 190

Preparation of Compound 393

[0736] NaH (9 mg. 0.22 mmol) was added to a solution of 393-1 (72 mg, 0.15 mmol) in DMF (1 mL) and stirred for 15 mins, lodomethane (18 uL, 0.29 mmol) was added, and the mixture was stirred at r.t. for 3 h. Lhe reaction was quenched with sat. NH4CI and extracted with EA. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated. Lhe crude was purified by chromatography on silica gel (EA:hexane) to give 393-2 (51 mg. 66%). LCMS: m/z 507.10 [M+H]⁺.

[0737] Potassium osmate (6 mg. 0.015 mmol) was added to a solution of 393-2 (51 mg. 0.10 mmol) and tert-butyl (tosyloxy)carbamate (41 mg, 0.15 mmol) in t-butanol (1 mL) and water (0.33 mL). and the solution was stirred overnight at r.t. The crude was

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PCT/US2014/051642 purified by chromatography on silica gel (EArhexane) to give 393-3 (0.025 g, 50%). LCMS: m/z 640.20 [M+I I]⁺.

[0738] HC1 (4N in dioxane. 1 mL) was added to 393-3 (0.025 g, 0.039 mmol), and the mixture was stirred for 1 h. The solvent was removed by evaporation and 4cyclopropoxy-3-methoxy benzoic acid (24 mg, 0.12 mmol), HATU (60 mg. 0.16 mmol), and diisopropylethylamine (40 uL. 0.23 mmol) were added, and the mixture was stirred at r.t. for 1.5 h. The crude was diluted with EA and washed with IN HC1. sodium bicarbonate and brine, dried over sodium sulfate and concentrated. The crude was purified by reverse phase HPLC to provide 393-4 (12 mg. 41%). LCMS: m/z 730.15 [M+H]⁺.

[0739] Pd/C (10%, 3 mg) was added to a solution of 393-4 (12 mg, 0.025 mmol) in EtOH (3 mL), and the mixture was stirred under hydrogen atmosphere for 2 h. The catalyst was removed by filtration, and the crude was purified by reverse phase HPLC to provide 393 (2.5 mg, 28%) LCMS: m/z 563.20 [M+H]⁺.

EXAMPLE 191

Preparation of Compound 394

[0740] Sodium iodide (40 mg, 0.27 mmol) was added to a solution of 393-4 (40 mg, 0.55 mmol) and chlorotrimethylsilane (35 uL, 0.27 mmol) in acetonitrile (3 mL), and the mixture was stirred at r.t. for 2 h. The reaction mixture was diluted with EA and washed with sat. Na₂(SO₂)3, and brine, dried over Na₂SC>4 and concentrated. The product was purified by reverse phase HPLC to provide 394. LCMS: m/z 597.15 [M+H]⁺.

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EXAMPLE 192

Preparation of Compound 395

[0741]

Compound 395-2 was prepared in a similar manner as 364. LCMS: m/z

706.20 [M+H]⁺. Compound 395 was prepared in a similar manner as 396. LCMS: m/z 607.10 [M+H]⁺.

EXAMPLE 193

Preparation of Compound 396

OH

[0742] Compound 396-2 was prepared in a similar manner as 364. LC/MS:m/z

714.20 [M+H], HC1 (4N in dioxane, 2 mL) was added to 396-2 (80 mg. 0.11 mmol.) and the mixture was stirred for 2 h. The mixture was concentrated to remove volatile components, and 396 was purified by reverse phase HPLC (11 mg. 15%). LCMS: m/z 615.15 [M+H]⁺.

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EXAMPLE 194

Preparation of Compound 397

[0743] Methanesulfonyl chloride (0.30 mL. 4.0 mmol) was added dropwise to a solution of 397-1 (0.70 g. 2.7 mmol) and diisopropvlethylamine (0.93 mL, 5.3 mmol) in CH₂C1₂ (30 mL) at 0 °C for 30 mins. The mixture was washed with IN HC1, and brine, dried over Na₂SO4 and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-2 (0.59 g, 85%). LCMS: m/z 349.95 [M+EI]⁺.

10744] Sodium cyanide (0.14 g, 2.8 mmol) was added to a solution of 397-2 (0.59 g. 2.3 mmol) in ethanol (10 mL) and water (2 mL). The mixture was heated at 50 °C for 30 mins. The mixture was diluted with EA and washed with water and brine, dried over Na^SCfi and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-3 (0.15 g. 23%). LCMS: m/z 280.95 [M+H]⁺.

[0745] NaH (65 mg, 1.6 mmol) was added to a solution of 397-3 (0.15 g, 0.54 mmol) in DMF (1 mL) and stirred for 5 mins. lodomethane (0.16 mL, 3.0 mmol) was added dropwise, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with NH4CI and extracted with EA. The organic extracts were washed with water and brine, dried over Na₂SC>4 and concentrated. The crude was purified by silica gel chromatography (eluent: EA:hexane) to provide 397-4 (0.123 g. 72%). LCMS: m/z 308.95 [M+H]⁺.

[0746] Borane-dimethylsulfide (0.11 mL, 0.11 mmol) was added dropwise to a solution of 397-4 (0.123 g, 3.9 mmol) in THF (2 mL). and the mixture was heated at 55 °C

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PCT/US2014/051642 for 1 h. The reaction was quenched with 6N HCI and heated at 55 °C for 15 mins. The volatile components were removed by evaporation, and 397-5 was used without further purification. LCMS: m/z 313.00 [M+H]⁺.

[0747] Benzyl chloroformate (85 uL. 0.P9 mmol) was added dropwise to a solution of 397-5 (3.9 mmol) and diisopropylethylamine (0.20 mL, 1.2 mmol) in CH2CI2 (2 mL), and the mixture was stirred at r.t. for 1 h. The mixture was diluted with EA and washed with water and brine, dried over NYSCL and concentrated. The crude was purified by silica gel chromatography (EA:hexane) to provide 397-6 (0.15 g, 87%). LCMS: m/z 447.05 [M+H]⁺.

[0748] Compound 397-7 was prepared in a similar manner as 364. LCMS:m/z

507.10 [M+H]⁺. Compound 397-8 was prepared in a similar manner as 377. LCMS:m/z

640.15 [M+H]⁺. Compound 397-9 was prepared in a similar manner as 377. LCMS:m/z

730.15 [M+H]⁺. Compound 397 was prepared in a similar manner as 394. LCMS:m/z

597.20 [M+H]⁺.

EXAMPLE 195

Preparation of Compounds 366, 367, 370, 373, 376, 389, 390, 391 and 392

Table 7

Example Method	Structure	LCMS: m/z
Compound 365	O'' , ° W ^H0 Ύ\|1 H \ F fif ^N Yv //%¼ ⁰ 366 Α <)	533.10 [M+H]⁺
Compound 424	cY NC, Ό. Jx. ^x. V r 1 h \ /^0H r if to JL to /to to-. AA γ Ύ Hto ~x_C\| ° 367 L' o	500.1 [M+H]⁺

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Example Method	Structure	LCMS: m/z
Compound 369	O' _/0.1. /^/^F Xm h^ho _v ^cF3 XT /^/ ^Cl 0 370 + (-, 1	555.10 [M+H]⁺
Compound 364	F O' _C/Xx a ///. /^f x x h ^h°_v ^cf3 r it A%aJX O 373 XX/Q	579.05 [M+H]⁺
Compound 364	O' ^°xS h x rxX XXX,nXCX^n^J^XX_c\| ⁰ 376 XX₀/	515.05 [M+H]⁺
Compound 388	O' ^/°X\ kA v/ Til h ^f3^c. ,°^h i \|\| AAC.^N /AA/- ^N Ax ° 389 ^A H	548.20 [M+H]⁺
Compound 388	a°xX hccoh rx^F X. /X /N. X, ,N. +/ A q' y ci ⁰ 390 A / 'N'^/ H	611.10 [M+H]⁺
Compound 388	OH O' X^-o 1 /+^-^F r il hnc oh xx X X. n X ,n. /X. X ΧΧγ /./X/ y /X/_Clo 391 XX ΧΧ'''/ H	628.20 [M+H]⁺

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Example Method	Structure	LCMS: m/z
Compound 388	vr il ^hFsCv^0H Γ f O 392 H	625.15 [M+H]⁺

EXAMPLE 196

Preparation of Compounds 246 and 247

[0749] Compound 370 (270 mg. 0.49 mmol) was separated via SFC to give two enantiomers; 246 (100 mg, 74.0%) and 247 (110 mg. 81.5%). 246; +ESI-MS;m/z 555.1 [M+H1⁺. 247; +ESl-MS;m/z 555.1 [Μ+Η]⁺.

EXAMPLE 197

Preparation of Compound 398

[0750] To a stirring mixture of 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid (70 mg. 0.31 mmol) in DMF (1.5 mL) were added HATU (90 mg, 0.237 mmol) and DIPEA (84 pL. 0.474 mmol). The mixture was stirred at r.t. for 10 mins. 2-amino-l-(6-(3-chloro-4fluorophenyl)-5-methoxypyridin-2-yl)-l-cyclopropylethan-l-ol in DMT (0.5 mL) as added. The mixture was stirred at for 10 mins, and then quenched with a 10% aq. solution of NaHCOj (10 mL). The mixture was diluted with DCM, and a normal aqueous work up with DCM was followed. The crude was purified via prep-HPLC to afford 398 as a white solid. TCMS: m/z 544.15 [M+H]⁺.

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EXAMPLE 198

Preparation of Compound 399

[0751] Compound 399 was prepared in a manner similar to 398. LCMS: m/z 716.2 [M+H]⁺.

EXAMPLE 199

[0752] To a stirring mixture of 400-1 (50 mg. 0.088 mmol, obtained during the preparation of 314) in DMF (2.0 mL) were added CS2CO3 (143 mg. 0.44 mmol) and Mel (38 mg. 0.264 mmol). The mixture was stirred at r.t. until the starting material was consumed. The crude was diluted EtOAc and water. The aqueous layer was extracted with EtOAc, dried over Na₂SO₄. filtered and concentrated under reduced pressure. Compound 400 was purified via HPEC to afford 400 as a white solid. ECMS: m/z 610.15 [M+H]⁺.

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EXAMPLE 200

Preparation of Compound 401

[0753] To a stirring mixture of 401-1 (460 mg, 1.6 mmol) in DMF (2.5 mL. deoxygenated) were added PdCfilPPhsfr (32 mg. 0.045 mmol), Cui (26 mg, 0.136 mmol), piperidine (0.35 mL) and trimethyl(prop-2-yn-l-yl)silane (180 mg, 1.6 mmol). The mixture subjected to micro wave irradiation at 60 °C for 3 h. The mixture was cooled to r.t. and diluted with EtOAc. The mixture was washed with brine, water and NaHCO3. The mixture was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 401-2 as a yellow solid. LCMS: m/z 198.05 [M+H]⁺.

[0754] To a stirring mixture of 401-2 (110 mg, 0.56 mmol) in DME (3 mL, deoxygenated) were added (3-chloro-4-fluorophenyl)boronic acid (191 mg, 1.1 mmol), PdCl?(dppf)2 and a solution of CS2CO3 (0.6 mL, 3.7 M). The mixture subjected to under microwave irradition at 110 °C for 4 h. The mixture was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified via a silica gel column to afford 401-3 as a white solid. TCMS: m/z 292.0 [M+H]⁺.

[0755] Compound 401-6 was prepared in 3 steps using methods similar to those for preparing 302. TCMS: m/z 321.0 [M+H]⁺. Compound 401-6 was coupled with 3

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PCT/US2014/051642 methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid followed by alcohol oxidation and deprotection to afford 401. LCMS: m/z 513. 05 [M+I I]^H.

EXAMPLE 201

Preparation of Compound 402

402-1

|0756| Diisopropylethylamine (24 uL, 0.14 mmol) was added to a solution of

402-1 (21 mg. 0.045 mmol), 3-methoxy-4-[(methylcarbamoyl)methoxy]benzoic acid (22 mg,

0.090 mmol) and HATU (38 mg, 0.099 mmol) in DMF (1 mL). and the mixture was stirred at

r.t. for 2 h. The mixture was diluted with EA, washed with IN HC1. water and brine, dried over N/bSOi and concentrated. The crude was purified by reverse-phase HPLC to provide

402 (7.5 mg). LCMS: m/z 586.05 [M+H]⁺.

EXAMPLE 202

Preparation of Compounds 403, 404 and 405

[0757] To a solution of 403-1 (6.0 g. 32.97 mmol) and K₂CO₃ (9.12 g, 66.1 mmol) in DMF (50 mL) was added 2-bromoacetonitrile (4.98 g, 39.52 mmol) dropwise. The mixture w as stirred at 80 °C for 4 h. The mixture was diluted with water, and extracted with EA (3 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous

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PCT/US2014/051642 sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (5-10% EA:PE) to give 402-2 as a colorless oil (5.1 g, 70 %).

[0758] To a solution of 402-2 (8.0 g, 36.2 mmol) in McOH:H₂O (2:1,90 mL) was added NaOH (2.9 g, 72.4 mmol), and the mixture stirred at 50 °C for 1 h. The mixture was diluted with water and extracted with EA (2 x 50 mL). The aqueous layer was acidified to pH 4.0 using 2.0 M HC1 solution. The aqueous phase was extracted with EA (2 x 150 mL). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated at low pressure to give 403-3 (5.6 g, 70%).

[0759] To a solution of 403-3 (530 mg, 2.35 mmol) in DMF (15 mL) were added DIPEA (590 mg, 7.04 mmol) and HATU (885 mg. 2.35 mmol), and the mixture was stirred at r.t. for 30 mins. The mixture was treated with 2-amino-1-(6-(3-bromo-4-fluorophenvl)-5niethoxypyridin-2-yl)ethanol (403-4, 800 mg, 2.35 mmol), and the mixture was stirred at r.t. for 2 h. The mixture w⁷as diluted with water, and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated at low⁷ pressure. The residue was purified by column chromatography on silica gel (PE:EA 1:1) to give 403-5 (1.0 g, 77.5%). +ESI-MS:m/z 547.9 [M+H]⁺.

[0760] To a solution of 403-5 (600 mg, 1.10 mmol) in DCM (20 mL) was added DMP (948 mg, 2.2 mmol) in portions, and the mixture was stirred at r.t. for 1 h. The mixture was washed with sat. Na₂S₂O₃ solution and brine. The organic phase was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to give 403-6 as a white solid (400 mg, 66.7%). +ESI-MS:m/z 546.1 [M+H]⁺.

[0761] To a solution of 403-6 (400 mg. 0.73 mmol) in THF (20 mL) was added CH₃MgBr (2.4 mL, 7.3 mmol) dropwise, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by prep-HPLC to give 403 (60 mg) as a white solid. +ESI-MS:m/z 562.1 [M+H]⁺.

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PCT/US2014/051642 [0762] Compound 403 (~45 mg) was separated via SFC separation to give two isomers: 404 (10.0 mg) and 405 (12.5 mg). 404: +ESI-MS:m/z 562.1 [M+H]⁺. 405: +ESIMS:m/z 562.0 [M+H]⁺.

EXAMPLE 203

Preparation of Compounds 406 and 407

[0763] To a solution of 406-1 (540 mg. 1.53 mmol) in THF (4 mL) was added cyclopropylmagnesium bromide (4 ml., 0.5M in THF) dropwise at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction was quenched with water, and extracted with EA (3 x 20 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4 and concentrated at low⁷ pressure. The residue was purified by chromatography (PE:EA 10:1) to give 406-2 (400 mg, 70%).

[0764] Compound 406-2 (400 mg. 1.0 mmol) was treated with concentrated ammonia water (10 mL) and ethanol (10 mL) in an autoclave. After sealing, the mixture was heated to 80 °C for 10 h with stirring. The mixture was cooled to r.t., and diluted with EA (30 mL). The mixture was washed with brine, dried over anhydrous Na2SO4 and concentrated at low pressure to give 406-3, which was used without further purification. +ESI-MS:m/z 337.1 [M+H]⁺.

[0765] Compound 406-6 was prepared essentially as described in the preparation of 403 by using 4-(2-fluoroethoxy)-3-methoxybenzoic acid and 406-3. The crude was purified by column chromatography (EA:PE 1:1) to give 406-4 as a white solid (201 mg. 73%). +ESI-MS:m/z 533.1 [M+H]⁺. Compound 406-4 was separated via SFC separation to give two isomers: 406 (60 mg) and 407 (65 mg). 406: +ESI-MS:m/z 533.1 [M+H]+. 407: +ESI-MS:m/z 533.1 [M+H]+.

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EXAMPLE 204

Preparation of Compounds 408 and 409

[0766] To a solution of 408-1 (560 mg, 0.2 mmol) in THF (4 mL) was added MeMgCl (1 mL, 3 M in Et₂O). The mixture was stirred at 0 °C for 1 h. The reaction was quenched with CBrj (5 g) in THF (10 mL). The mixture was diulted with EA (50 mL). Lhc solution was washed with brine, dried over anhydrous Na₂SC>4 and concentrated at low pressure. The residue was purified by silical gel to give 408-2 (402 mg, 70%). +ESI-MS:m/z 577.1 [M+H]⁺.

[0767] Under N₂ atmosphere, a 50 mL flask with a magnetic stirring bar was charged with 208-3 (300 mg. 0.75 mmol), 408-2 (290 mg, 0.5 mmol). Pd(dppf)Cl₂ (8 mg, 1 mmol%), KF (180 mg. 3.0 mmol), and dioxane:H₂O (20 mL:5mL). The mixture was stirred for 10 h at 100 °C. The mixture was cooled to r.t. and diluted with water (50 ml.) and F.A (50 mL). The organic layer was separated, and the aqueous phase was extracted with EA (2 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 408-3 as a solid (280 mg. 70%). +ESI-MS:m/z 774.5 [M+H]⁺.

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PCT/US2014/051642 [0768] To a solution of 408-3 (280 mg, 0.36 mmol) in dioxane (8 mL) wad added conc.IICl (2 mL). Lhe mixture was stirred at 80 °C for 1 h. Lhe mixture was cooled to r.t.

and diuted with water (15 mL) and EA (20 mL). The organic phase was washed with brine, dried over anhydrous NazSCq and concentrated at low pressure. The residue was purified by prep-HPLC to give 408-4 (189 mg).

[0769] Compound 408-4 (189 mg) was separated via SFC separation to give two enantiomers: 408 (60 mg) and 409 (65 mg). 408: +ESI-MS:m/z 524.1 [M+H]⁺. 409: +ESIMS:m/z 524.1 [M+H]⁺.

EXAMPLE 205

Preparation of Compounds 410 and 411

SEM

SEM [0770] Compound 410-3 was prepared essentially as described in the preparation of 403 by using 410-1 and 410-2. The crude was purified by column chromatography on silica gel (PE:acetone 5:1) to give 410-3 (1.8 g. 89 %). +EST-MS:m/z 628.1 [M+H]⁺.

[0771] Compound 410-4 was prepared essentially as described in the preparation of 403. Crude 410-4 was obtained (0.8 g, 52.3%). +ESI-MS:m/z 626.1 [M+H]⁺. Compound 410-5 was prepared essentially as described in the preparation of 403. Crude 410-5 was purified by column chromatography on silica gel (PE:acetone 5:1) to give 410-5 (496 g. 51 %). +ESI-MS:m/z 642.1 [M+H]⁺. Compound 410-5 was prepared essentially as described in the preparation of 403. Crude 410-6 was purified by prep-HPLC to give 410-6 (302 mg, 70

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%). +ESI-MS:m/z 512.1 [M+H] . Compound 410-5 was separated via SFC separation to give 410 (30 mg) and 411 (28 mg). 410: +ESI-MS:m/z 512.1 [M+H]⁺. 411: +ESl-MS:m/z 512.1 [M+H]⁺.

EXAMPLE 206

Preparation of Compounds 412 and 413

[0772] Compounds 412 and 413 were prepared essentially as described in the preparation of 403 by using 412-1 and ethynyl magnesium bromide. The product was purified by prep-HPLC and SFC separation. 412 (30 mg) and 413 (32 mg) were obtained as white solids. 412: +EST-MS:m/z 516.9 [M+H]⁺. 413: +EST-MS:m/z 516.9 [M+H]⁺.

EXAMPLE 207

Preparation of Compounds 414, 415 and 416 oh 'to

414, 415 &416 [0773] Racemic 414 was prepared essentially as described in the preparation of 403 by using 412-1 and (7?)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Compound 414 was obtained as a white solid (150 mg). Compound 414 was separated via SFC separation to give two enantiomers: 415 (35 mg) and 416 (38 mg). 415: +ESI-MS:m/z 519.1 [M+H]⁺. 416: +ESI-MS:m/z 519.0 [M+H]⁺.

EXAMPLE 208

Preparation of Compounds 417 and 418 oh 'to

[0774] Compounds 417 and 418 were prepared essentially as described in the preparation of 403 by using 412-1 and (S)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid.

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Compounds 417 (36 mg) and 418 (39 mg). 417: +ESI-MS:m/z 518.9 [M+H]⁺. 418: +ES1MS:m/z 518.9 [M+I I]^H.

EXAMPLE 209

Preparation of Compounds 419, 420 and 421

[0775] To a solution of 419-1 (1.0 g, 2.32 mmol) in dioxane:! I₂O (4:1. 20 mL) was added NaHCCf (584.6 mg, 6.96 mmol) in one portion and Boc₂O (657.5 mg, 3.02 mmol) in portions. The mixture was stirred at r.t. for 2 h. and then diluted with water (50 mL) and EA (50 mL). The aqueous phase was extracted by EA (2 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue was purified by column chromatography on silica gel (PE:EA 4:1) to give 419-2 (1.2 g, 97%). +ESI-MS:m/z 532.3 [M+H]\ [0776] To a solution of 419-2 (1.2 g, 2.26 mmol) in DCM (20 mL) was added DMP (1.95 g. 4.52 mmol) in portions. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. Na₂SO3 solution (50 mL), and extracted with CH₂C1₂ (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by chromatography to give 419-3 as a white solid (1.0 g, 83.3%). +ESI-MS:m/z 530.3 [M+H]⁺.

[0777] To a solution of 419-3 (1.0 g, 1.89 mmol) in THF (15 mL) was added CHjMgBr (6.30 mL. 18.90 mmol) dropwise at 0 °C. and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The

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PCT/US2014/051642 combined organic phase was dried over anhydrous sodium sulfate and concentrated at low pressure. The crude was purified by column chromatography (PE:EA 3:1-2:1) to give 419-4 as a white solid (605 mg, 58.3%). +ESI-MS:m/z 546.2 [M+H]⁺.

[0778] To a solution of 419-4 (600 mg, 1.1 mmol) in dioxane (16 mL) was added cone. HC1 (8 mL). The mixture was stirred at 80 °C overnight. After cooled to r.t.. the mixture was neutralized by sat. NaHCCf solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give 419-5 (301 mg, 87%).

[0779] Compound 419 was prepared essentially as described in the preparation of 403 by using 419-5 and 4-(2-amino-2-oxoethoxy)-3-methoxybenzoic acid. Compound 491 was obtained as a white solid (90 mg). +ESI-MS:m/z 523.1 [M+H]⁺.

[0780] Compound 419 (90 mg, 0.172 mmol) was separated via SFC separation to give two enantiomers: 420 (15.0 mg) and 421 (22.0 mg). 420: +ESI-MS:m/z 523.1 [M+H]⁺. 421: +ESl-MS:m/z 523.1 [M+H]⁺.

EXAMPLE 210

Preparation of Compounds 422 and 423

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PCT/US2014/051642 [0781] To a solution of 422-1 (100 mg, 0.575 mmol) in THF (10 mL) was NaBHi (44 mg, 1.1 mmol) was added, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched by water, and extracted with EA (3 x 20 mL). The organic phase was washed with brine, dried over anhydrous lYoSCh and concentrated at low pressure. The crude was purified by chromatography (PE:EA 20:1 to 5:1) to afford 422-2 (90 mg. 89.1 %).

[0782] To a solution of 422-2 (534 mg, 3.0 mmol), methyl 4-hydroxy-3methoxybenzoate (546 mg, 3.0 mmol) and PPh₃ (786 mg. 3.0 mmol) in THF (15 mL) at 0 °C was added D1AD (606 mg. 3.0 mmol) dropwise. The mixture was stirred at r.t. for 2 h. The reaction was quenched with sat. NaHCO₃ solution. The mixture was extracted with DCM (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. Tire residue was purified by flash column chromatography on silica gel to give 422-3 (667 mg, 66%).

[0783] A solution of 422-3 (2.0 g, 5.85 mmol) and Pd(OH)₂ (0.2 g) in MeOH (20 mL) was stirred under IL atmosphere (50 psi) at r.t. overnight. The mixture was filtered, and the filtrate was evaporated to give crude 422-4 (1.5 g), which was used without further purification.

[0784] To a solution of 422-4 (150 mg. 0.597 mmol) in THF (10 mL) at 0 °C was added NaH (47.8 mg. 1.195 mmol), and the mixture was stirred at 0 °C for 0.5 h. The mixture was treated with SEMC1 (149 mg. 0.896 mmol), and the mixture was allowed to warm to r.t. over 30 mins. The reaction was quenched with water, and extracted with EA (2 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₃SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA 20:1) to give 422-5 (110 mg. 48.2 %).

[0785] To a solution of 422-5 (600 mg, 1.57 mmol) in co-solvent TIIIHLO (1:1. 10 mL) was added NaOH (126 mg. 3.14 mmol in 2 mL water). The mixture was stirred at r.t. for 1 h. The organic solvent was evaporated under reduced pressure, and the aqueous layer was acidified to pH 4~5 with IM HCI solution. The mixture was extracted with EA (2 x 20 mL). The combined organic phase was dried over anhydrous sodium sulfate and concentrated at low pressure to give 422-6 (480 mg, 83.0 %).

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PCT/US2014/051642 [0786] Compound 422-8 was prepared essentially as described in the preparation of 403 by using 422-6 and 422-7. Compound 422-8 was obtained as a white solid (180 mg, 66.9 %). +EST-MS:m/z 661.0 [M+H]⁺.

[0787] A suspension of 422-8 (180 mg, 0.273 mmol) in HCkdioxane (4M, 15 mL) was stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure to give crude 422-9. The residue was diluted with sat. NaHCOs (10 mL). and extracted with EA (2x10 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 5:1 to 1:1) to give 422-9 (90 mg, 62.3 %).

[0788] Compound 422-9 (90 mg) was separated by SFC separation to give two enantiomers: 422 (25 mg) and 423 (27 mg). 422: +ESI-MS:m/z 531.0 [M+H]⁺. 423: +ESIMS:m/z 531.0 [M+H]⁺.

EXAMPLE 211

Preparation of Compound 424

[0789] To a solution of 424-1 (1.05 g, 3.0 mmol) and 18-crowm-6 (800 mg. 3.1 mmol) in CHjCN (50 mL) was added CsF (900 mg. 6.0 mmol). The mixture was heated to reflux for 1 h and the concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:1) to provide 424-2 as a white sol id (360 mg. 40 %).

[0790] A 50 mL round bottom flask with a magnetic stirring bar was charged with 424-2 (360 mg. 1.2 mmol), MeNCF (5 mL) and EtjN (303 mg, 3.0 mmol). The mixture was stirred at r.t. for 10 h and then concentrated under reduced pressure. The residue was purified by column chromatography (PE:DCM 2:1) to give 424-3 (270 mg, 63%).

[0791] To a stirred mixture of 424-3 (271 mg, 0.75 mmol) and NiCf (127 mg, 1 mmol) in MeOH (10 mL) was added NaBFL (380 mg. 1.0 mmol) in portions until the starting materials was consumed. The mixture was concentrated under reduced pressure, and the

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PCT/US2014/051642 residue was purified by column chromatography (EA:EtOH 10:1) to give 424-4 as a colorless oil (130 mg, 50%). +ESI-MS:m/z 328.8 [M+I I].

[0792] Compound 424 was prepared essentially as described in the preparation of 403 by using the 424-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid. The product was purified by prep-HPLC. Compound 424 was obtained as a white solid (180 mg, 66.9 %). +ESI-MS:m/z 523.2 [M+H]⁺.

EXAMPLE 212

Preparation of Compound 425

[0793] Compound 425-3 was prepared essentially as described in the preparation of 403 by using 425-1 and 425-2. The crude was purified by column chromatography (PE:EA 1:1) to give 425-3 (190 mg). +ESl-MS:m/z 654.9 [M+H]⁺.

[0794] To a solution of 425-3 (190 mg, 0.29 mmol) in dioxane (15 mL) was added cone. HC1 (5.0 mL). The mixture was stirred at r.t. for 1 h, neutralized with sat. NaHCOa solution and extracted with EA (3 x 10 mL). The organic layer was dried over anhydrous sodium sulfate, and concentrated at low pressure. The residue was purified by prep-HPLC to give 425 (21 mg, 13.5%) as a white solid. +ESI-MS:m/z 534.9 [M+H]⁺.

EXAMPLE 213

Preparation of Compound 426

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PCT/US2014/051642 [0795] To a stirred solution of 426-1 (16.2 g, 90mmol) in HC1 (6 Λ; 300 mL) at 0 °C was added a solution of NaN()> (6.90 g, 99 mmol) in water (15 mL) dropwise. The mixture was stirred at 0 °C for 1 h and then treated with a solution of KI (75 g, 450 mmol) in water (150 mL). The mixture was stirred for 30 mins and then extracted with ΕΛ (4 x 100 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 426-2 (21.2 g. 80.5%) as a light yellow solid.

[0796] To a suspension of 426-2 (8.77 g, 30 mmol), Cui (1.14 g, 6 mmol), PdCl₂(PPh3)₂ (1.05 g, 1.5 mmol) and NEtj(21 ml.. 150 mmol) in THF(15O mL) was added propiolic alcohol (3.36 g, 60 mmol) under N₂ atmosphere. The mixture was stirred at r.t. overnight and then filtered through a celite pad. The filtrate was concentrated to dryness and the residue was diluted with EA (200 mL). The solution was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 1:1) to give 426-3 (5.1 g, 77.3%) as a light yellow solid.

[0797] To a solution of 426-3 (2.2 g, 10 mmol) in MeOH (100 mL) was added Pd/C (0.5 g) under N₂. The mixture was degassed and refilled with hydrogen (3x). The mixture was stirred under IF atmosphere (40 psi) overnight. The mixture was filtered through a celite pad and the filtrate was concentrated in vacuum to give crude 426-4. The residue was purified by column chromatography on silica gel (PE:EA 1:1) to give 426-4 (1.62 g, 72.3%) as a light yellow oil.

[0798] To a solution of 426-4 (0.67 g. 3 mmol) in EtOH (7.5 mL) and water (2.5 mL) was added NaOH (0.48 g. 12 mmol). The mixture was stirred at 50 °C for 1 h. cooled to 0 ⁽’C, and acidified to pH 5 with HC1 (2 M) solution. The mixture was extracted with EA (4 x 50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated in vacuum to give 426-5 (0.50 g. 80.0%) as a yellow solid, which was used without further purification.

[0799] Compound 426 was prepared essentially as described in the preparation of 403 by using 426-5 and 2-ammo-l-(6-(3-chloro-4-fluorophenyl)-5-methoxypyridin-2-yl)-l-264WO 2015/026792

PCT/US2014/051642 cvclopropylethanol. The crude was purified by prep-HPLC to give 426 (35 mg, 13.3%) as a white solid. +ESI-MS:m/z 529.0 [M+11] f

EXAMPLE 214

Preparation of Compound 427

[0800] To a suspension of 427-1 (1.0 g. 4.67 mmol) in dioxane (30 mL) were added 427-2 (2.37 g, 9.346 mmol), AcOK (1.37 g, 14.0 mmol) and Pd(dppf)Cb (0.346 g, 0.467 mmol). The mixture w^ras stirred at 80 °C under N₂ atmosphere for 16 h. The mixture was cooled to r.t.. poured into water (100 mL), and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 50:1) to give 427-3 (1.4 g. contain 0.3-0.4 g of 427-2).

[0801] To a solution of 427-4 (310 mg, 0.554 mmol) in THF (10 mL) at 0 °C was added cyclopropyl-magnesium bromide (11 mL, 0.5 M in THF) dropwise. The mixture was stirred for 1 h and then warmed to r.t. The reaction was quenched with sat. NH4CI (10 mL) solution, and extracted with EA (2 x 20 mL). The combined organic phase was washed with sat. NaHCOj solution, and brine. The organic layer was dried over anhydrous Na₂SC>4 and concentrated at low pressure. The residue was purified by column chromatography on silica gel (30% EA in PE) to give 427-5 (170 mg, 51.0 %). +ESI-MS:m/z 601.1 [M+H]⁺.

[0802] To a suspension of 427-5 (120 mg, 0.2 mmol) in a mixture of dioxane and H₂O (9:1, 10 mL) were added CS2CO3 (195.6 mg, 0.6 mmol), 427-3 (108.6 mg, 0.3 mmol) and Pd(dppf)Cl₂ (16.3 mg, 0.02 mmol) under N? atmosphere. The mixture was stirred at 70

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PCT/US2014/051642 ^l’C for 2 h. The mixture was cooled to r.t., poured into water (50 mL) and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous

NaiSOi and concentrated at low pressure. The residue was purified by column chromatography (10-30% EA in PE) to give 427-6 (121 mg. 92.2 %). +ESI-MS:m/z 657.1 [M+H]⁺.

[0803] A suspension of 427-6 (121 mg, 0.184 mmol) and Pd/C (20 mg) in MeOH (20 mL) was stirred under IL atmosphere (balloon) at r.t. overnight. The solution was filtered, and the filtrate was concentrated in vacuum. The residue w^ras purified by prepHPLC to give 427 (17 mg, 10.1%) as a white solid. +ESI-MS:m/z 539.1 [M+H]⁺.

EXAMPLE 215

Preparation of Compound 428

[0804] Compound 428-2 was prepared as provided in Mello et al., J. Am. Chem. Soc. (2005) 127(29):10124-10125, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 428-2. Compound 428-3 was prepared as provided in PCT Publication No. WO 2002/034745. published May 2. 2002. which is hereby

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PCT/US2014/051642 incorporated by reference for the limited purpose of its description of the preparation of 4283.

[0805] To a solution of 428-3 (8 g, 38 mmol) in DMF (100 mL) were added K2CO3 (9.5 g. 69 mmol) and NaN₂ (3 g. 46 mmol) at r.t. The solution was stirred for 2 h. poured into H₂O (100 mL) and extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 428-4 (5.1 g, 66.1%).

[0806] To a solution of 428-4 (5 g, 23.4 mmol) in EtOH (50 mL) were added Boc₂O (6.11 g. 28 mmol) and Pd/C (1 g) at r.t. under N₂. The solution was degassed and refilled with H₂ (3x). The mixture was stirred at r.t. under H₂ atmosphere (balloon) for 18 h. The solution was filtered, and the filtrate was concentrated to dryness. The residue was purified by chromatography on silica gel (PE:EA 10:1) to give 428-5 (2.2 g, 34.4%).

[0807] To a solution of 428-5 (2.2 g, 7.9 mmol) and (3-chloro-4fluorophenyl)boronic acid (1.39 g, 7.9 mmol) in a mixture of dioxane and H₂O (20 mL/5 mL) were added Pd(dppf)Cl₂ (289 g.0.395 mmol) and K₂COj (1.63 g. 11.85 mmol). The mixture was degassed and refilled with N₂ (3x). The mixture was stirred under N₂ at 40 °C for 3 h. The mixture was cooled to r.t., and diluted with EA (100 mL) and water (100 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 428-6 (2.923 g, 100%) as a white solid. +ESI-MS:m/z 370.8 [M+H]⁺.

[0808] To a solution of 428-6 (1.2 g, 3.24 mmol), tributyl(l-ethoxyvinyl)stannane (2.34 g, 6.48 mmol) and KF (751 mg, 12.96 mmol) in DMF (15 mL) was added Pd(dppf)Cl₂(237 mg, 0.324 mmol) under N₂. The mixture was stirred at 80 °C for 2 h. After cooling to r.t., the mixture was diluted with EA (100 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure to give crude 428-7 (1.35 g crude), which was used in the next step directly. +ESI-MS:m/z 407.1 [M+H]⁺.

[0809] Compound 428-7 (1.315 g, 3.24 mmol) was dissolved in THF (20 mL) and H₂O (2 mL). The solution was treated with NBS (1.13 g, 6.4 mmol) at r.t., and stirred for

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PCT/US2014/051642 mins. The mixture was concentrated at low pressure, and the residue was purified by column chromatography on silica gel (PE:EA 10:1) to give 428-8 (1.4 g, 94.5%). +ESIMS:m/z 459.1 [M+H]⁺.

[0810] Compound 428-9 was prepared essentially as described in the preparation of 406 by using 428-8. Crude 428-9 (410 mg, 63%) was used directly in the next step. Compound 428-10 was prepared essentially as described in the preparation of 406 by using crude 428-9. Crude 428-10 (205 mg, 57.6%) was used directly in the next step. +ESIMS:m/z 436.3 [M+HJL Compound 428-11 was prepared essentially as described in the preparation of 406 by using crude 428-10 and 3-methoxy-4-(2-((4methoxybenzyl)oxy)ethoxy)benzoic acid. Crude 428-11 was purified by column chromatography on silica gel (50% EA in PE) to give purified 428-11 (106 mg, 30.1 %).

[0811] To a solution of 428-11 (100 mg, 0.13 mmol) in dioxane (2 mL) was added cone. HC1 (2 mL) at r.t.. and the mixture was stirred for 30 mins. The mixture was neutralized using a sat. NaoCCF, solution, and extracted will) EA (3 x 10 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂S() ι and concentrated at low⁷pressure. The residue was purified by prep-HPLC to give 428 (15 mg, 21.2%) as a w⁷hite solid. +ESI-MS:m/z 530.0 [M+H]⁺.

EXAMPLE 216

Preparation of Compounds 429, 430 and 431

Cl

429, 430 & 431 [0812] Compound 429 was prepared essentially as described in the preparation of 403 by using 403-3 and 406-3. Compound 429 was obtained as a w⁷hite solid (50 nig). +ESIMS:m/z 544.1 [M+H]⁺.

[0813] Compound 429 w⁷as separated via SFC separation to give two enantiomers: 430 (3.22 mg, 12.9%) and 431 (3.45 mg. 13.8%). 430: +ESl-MS:m/z 544.1 [M+H]⁺. 431: +ESl-MS:m/z 544.1 [M+H]⁺.

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EXAMPLE 217

Preparation of Compound 432

[0814] To a solution of 432-1 (2.0 g, 10.99 mmol) in DMF (20 mL) were added ClCF2COONa (3.0 g, 19.74 mmol) and K2CO3 (4.4 g. 31.88 mmol). The mixture was stirred at 95 °C for 5 h. After cooling to r.t., the mixture was poured into water (100 mL) and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated at low' pressure. The residue was purified by column chromatography on silica gel (5-20% EA in PE) to give 432-2 (1.3 g, 51.0%).

[0815] Compound 432-3 was prepared essentially as described in the preparation of 426 using 432-2. Compound 432-3 was obtained as a white solid (1.19 g. 97.5%). Compound 432 was prepared essentially as described in the preparation of 406 by using 4323 and 432-4. Compound 432 was obtained after purification by prep-HPLC as a white solid (70 mg, 21.7%). +ESl-MS:m/z 537.1 [M+H]⁺.

EXAMPLE 218

[0816] To a solution of 433-1 (2 g, 6.8 mmol), potassium trifluoro(vinyl)borate (0.917 mg, 6.8 mmol) and Et₃N (1.73 g, 17.12 mmol) in MeOH (30 mL) was added

Pd(dppf)C12 (497 mg, 0.68 mmol) under N₂. The mixture was stirred under 1% at 70 °C for

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h. The solution was cooled to r.t., and diluted with EA (100 mL) and water (50 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography on silica gel (3% EA in

PE) to give 433-2 as a colorless oil (1.1 g, 84.6%).

[0817] To a solution of 433-2 (730 mg. 3.84 mmol) in THF (15 mL) was added Bl I ; · THF (4 mL, 1 M) at 0 °C, and the reaction was stirred at 0 °C for 1 h. The solution was treated with NaOH (10 mL, 1 M in water) and H2O2 (3 mL) at 0 °C. The mixture was stirred at r.t. for 1 h, and extracted with ΕΛ (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 433-3 (320 mg. 40.4%).

[0818] Compound 433-4 was prepared essentially as described in the preparation of 426 using 433-3. Compound 433-4 obtained as a white solid (210 mg, 70.7%). Compound 433 was prepared essentially as described in the preparation of 406 by using 4334 and 433-5. Compound 433 was obtained after purification by prep-HPLC as a white solid (32 mg. 8.2%). +ESI-MS:m/z 515.0 [M+H]⁺.

EXAMPLE 219

[0819] Compound 434-2 was prepared as described in PCT Publication No. WO 2009/055077, published on April 30. 2009. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 434-2.

[0820] To a suspension of 1, 2, 4-triazole (0.52 g, 7.51 mmol), and K2CO3 (2.57 g. 20.49 mmol) in DMF (15 mL) w'as added 434-2 (1.77 g. 6.83 mmol) at 0 °C. and stirred at r.t. overnight. The mixture was poured into water (100 mL), and extracted by EA (4 x 100

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PCT/US2014/051642 mL). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated at low pressure. The residue was purified by column chromatography [0821] Compound 434-4 was prepared essentially as described in the preparation of 426 by using 434-3. Compound 434-4 was obtained as a white solid (0.4 g. 57.2%). Compound 434 was prepared essentially as described in the preparation of 406 by using 4344 and 434-5. Compound 434 was obtained after purification by prep-HPLC as a white solid (135 mg, 27.2%). +EST-MS:m/z 552.1 [M+H]⁺.

[0822] To a solution of 435-1 (270 mg, 0.75 mmol) in DCM (10 mL) was added BAST (220 mg, 1.0 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. NaHCCh solution (20 mL). extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Crude 435-2 (271 mg, 99 %) was used without further purification.

[0823] To a solution of 435-2 (271 mg. 0.75 mmol) and NiCl? (127 mg, 1 mmol) in MeOH (10 mL) was added NaBLU (380 mg. 1.0 mmol) in portions until the starting materials was consumed. The reaction was quenched by water (10 mL), and extracted with EA (3 x 30 mL). The organic phase was washed with brine, dried over anhydrous NaiSOq, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (10% EtOH in EA) to give 435-3 as a colorless oil (130 mg, 50%). +ESI-MS:m/z 331.1 [M+H]⁺.

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PCT/US2014/051642 [0824] Compound 435 was prepared essentially as described in the preparation of

406 by using 435-4 and 435-5. Compound 435 was obtained after purification by prepHPLC as a white solid (85 mg, 47%). +ESI-MS:m/z 525.2 [M+HJ⁺.

EXAMPLE 221

Preparation of Compound 436

[0825] To a stirred solution of 436-1 (800 mg, 2.02 mmol) and PI1SO2CHF2 (465 mg, 2.42 mmol) in THF (10 mL) was added LDA (2 mL. 4 mmol) dropwise at -78 °C under Nt atmosphere. The mixture was stirred at -78 °C for 2 h, and warmed to 0 ^UC for 30 mins. The reaction w⁷as quenched with sat. NH4CI solution, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous NtoSOi and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 3:1) to give 436-2 (610 mg, 51.6%). +ESI-MS:m/z 587.1 [M+IIJ¹.

[0826] To a solution of 436-2 (610 mg, 1.04 mmol) in DMF (5 mL) were added HOAc (1 mL) and H2O (1 mL) at r.t. The mixture was treated with magnesium (250 mg. 10.4 mmol) in portions. After stirring at r.t. for 6 h, the mixture was poured into ice-water (50 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure to give 436-3 (320 mg, 68.9 %). +ESl-MS:m/z 446.9 [M+H]⁺.

[0827] To a solution of 436-3 (320 mg, 0.72 mmol) in FA (3 mL) w⁷as added HC1/EA (3 mL. 4M). The solution was stirred at r.t. for 30 mins, and then concentrated to dryness. Crude 436-4 (220 mg. 90.9%) was used without purification.

[0828] Compound 436 was prepared essentially as described in the preparation of 406 by using 436-4 and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid. Compound 436 was

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PCT/US2014/051642 obtained after purification by prep-HPLC as white solid (40 mg, 11.7%). +ESI-MS:m/z

541.0 [M+H]⁺.

EXAMPLE 222

Preparation of Compound 437

[0829] To a solution of 437-1 (1.0 g, 5.5 mmol) and K₂CO₃ (1.0 g, 7.3 mmol) in a mixture of CH3CN (10 mL) and H₂O (2 mL) was added 2-bromo-1.1 -difluoroethene (10.0 mL, ~2 M in acetonitrile) at 0 °C. The mixture was stirred at 50 °C for 10 h. After cooling to r.t. the mixture was poured into water (50 mL) and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 437-2 as an oil (0.4 g crude).

[0830] To a solution of 437-2 (0.4 g, 1.2 mmol) in MeOH (20 mL) was added Pd/C (0.3 g) under N₂. The suspension was degassed and refilled with H₂ (3x). The mixture was stirred under H₂ (50 psi) at r.t. for 5 h. The suspension was filtered through a Celite pad. and the filtrate was concentrated to dryness. The residue was purified by column chromatography (PE:EA 9:1) to give 437-3 as a white solid (250 mg, 84.7%).

[0831] Compound 437-4 was prepared essentially as described in the preparation of 426 by using 437-3. Compound 437-4 was obtained as a white solid (201 mg, 85.1%). Compound 437 was prepared essentially as described in the preparation of 406 by using 4374 and 437-5. Compound 437 was obtained after purification by prep-HPLC as white solid (50 mg. 36.4%). +ESl-MS:m/z 551.2 [M+H]⁺.

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EXAMPLE 223

Preparation of Compound 438

[0832] Compound 438-1 was prepared in a similar manner as 434. Compound

438-4 was prepared in a similar manner as 406. Compound 438 was prepared essentially as described in the preparation of 434 by using 438-3 and 438-4. Compound 438 was obtained after purification by prep-HPLC as white solid (230 mg, 23%). +ESI-MS:m/z 551.0 [M+HJ¹.

EXAMPLE 224

Preparation of Compound 439

[0833] To a solution of 439-6 (2.334 g, 6 mmol) in DMF (20 mL) were added

Ν,Ο-dimethyl-hydroxylamine hydrochloride (873 mg, 9 mmol), DIPEA (2.322 g, 18 mmol) and HATU (3.42 g, 9 mmol), and the mixture was stirred at r.t. for 1 h. The mixture was

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PCT/US2014/051642 poured into water (50 mL), and extracted with EA (3 x 50 mL). The combined organic layer was washed with brine, dried over anhydrous NajSCL and concentrated under reduced pressure. The residue was purified by column chromatography (20-50% EA in PE) to give

439-7 (2.4 g, 92.7 %). +ESI-MS:m/z 433.1 [M+H]⁺.

[0834] Compound 439-2 was prepared essentially as described in the preparation of 428 by using 439-1 and 3-chloro-4-fluorophenylboronic acid. Compound 439-2 was obtained as a white solid (0.61 g. 69.0 %). Compound 439-3 was prepared essentially as described in the preparation of 426 by using 439-2. Compound 439-3 was obtained as a white solid (0.97 g, 58.8%).

[0835] To a solution of 439-3 (1.6 g. 4.8 mmol) and 439-7 (2.1 g, 4.8 mmol) in anhydrous THF (20 mL) was added isopropyl-magnesium chloride (18.5 mL. 24.1 mmol) dropwise at 0 °C, and the mixture was stirred at r.t. for 1 h. The mixture was quenched with water, and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na;SOj and concentrated under reduced pressure. The residue was purified by column chromatography (10-50% EA in PE) to give 439-4 (1.2 g. 64 %). +ESl-MS:m/z 578.0 [M+H]⁺.

[0836] Compound 439-5 was prepared essentially as described in the preparation of 403 by using 439-4. Compound 439-5 was obtained as a white solid (160 mg, 27.0 %). +ESl-MS:m/z 594.0 [M+H]+. Compound 439 was prepared essentially as described in the preparation of 425 by using 439-5. Compound 439 was obtained as a white solid (101 mg, 79.2 %). +EST-MS:m/z 473.8 [M+H]⁺.

EXAMPLE 225

Preparation of Compound 440

F O

Cl [0837] Compound 440 was prepared essentially as described in the preparation of

406 by using 2-bromo-l-(6-(3-chloro-4-fluorophenyl)-4-ethylpyridin-2-yl)ethanone.

Compound 440 was obtained as a white solid (197 mg, 73%). +ESl-MS:m/z 523.1 [M+H]⁺.

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EXAMPLE 226

Preparation of Compound 441

[0838] Compound 441 was prepared essentially as described in the preparation of

428 by using 2,4-dibromothiazole. Compound 441 was obtained as a while solid (60 mg.

35.7 %). +ESI-MS:m/z 480.8 [M+H]⁺.

EXAMPLE 227

Preparation of Compound 442

[0839] Compound 442-1 was prepared as essentially described in the preparation of 436. Compound 442-2 was prepared as essentially described in the preparation of 403. Compound 442 was prepared essentially as described in the preparation of 406 by using 4421 and 442-2. Crude 442 was purified by prep-HPLC to give 442 as a white solid (65 mg. 13.3%). +ESI-MS:tn/z 554.1 [M+H]⁺.

EXAMPLE 228

[0840] To a solution of 443-1 (511 mg, 1.27 mmol) in anhydrous DMF (5 mL) were added TMS-CFj (217 mg, 1.53 mmol) and LiOAc (8.4 mg, 0.127 mmol) at r.t., and the mixture was stirred for 24 h. The mixture was treated with HCI (1.5 mL, 1 M) solution, and

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PCT/US2014/051642 stirred at r.t. for 1 h. The mixture was diluted with water (20 mL), and extracted with EA (2 x 40 mL). The combined organic layers were washed with brine, dried over anhydrous

NaiSOi and concentrated under reduced pressure. The residue was purified by flash column chromatography (PE:EA 5:1) to give 443-2 (131 mg, 21.8%).

[0841] Compound 443 was prepared essentially as described in the preparation of

428 by using 443-2 and 442-2. Compound 443 was obtained as a white solid (92 mg.

53.2%). +ESI-MS:m/z 616.0 [M+H]⁺.

EXAMPLE 229

Preparation of Compound 444

[0842] Compound 444 was prepared essentially as described in the preparation of

406 by using 444-1 and 444-2. Compound 444 was purified by prep-HPLC to give 444 as a white solid (55 mg, 25.4%). +ESI-MS:m/z 555.0 [M+H]⁺.

EXAMPLE 230

Preparation of Compound 445

[0843] Compound 445 was prepared essentially as described in the preparation of

406 by using 445-1 and 445-2. Compound 445 was purified by prep-HPLC to give 445 as a white solid (56 mg, 36.3%). +ESl-MS:m/z 537.0 [M+H]⁴.

EXAMPLE 231

Preparation of Compounds 446 and 447

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PCT/US2014/051642 [0844] Compound 442 (60 mg) was separated via SFC separation to give two isomers: 446 (25 mg) and 447 (25 mg). 446: +ESI-MS:m/z 554.0 [M+H]⁺. 447: +ESIMS:m/z 554.1 [M+H]⁺.

EXAMPLE 232

Preparation of Compound 448

[0845] Compound 448-2 was prepared essentially as described in Jang et al., Tel. Lett. (2006) 47(50):8917-8920, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 448-2. To a suspension of 448-2 (6.0 g. 22.9 mmol) and K2CO3 (6.3 g, 45.6 mmol) in CH3CN (40 mL) was added Met (6.5 g, 45.6 mmol) at r.t. The solution was heated to 80 °C and stirred for 8 h. The precipitate was removed by filtration, and the organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 20:1) to give 448-3 (5.5 g, 87.3%) as a white solid.

[0846] Compound 448 was prepared essentially as described in the preparation of 428 and 443 by using 448-3 and 448-4. Crude 448 was purified by prep-HPLC to give 448 as a white solid (40 mg, 51.9%). +ESI-MS:m/z 554.0 [M+H]⁺.

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EXAMPLE 233

Preparation of Compounds 449 and 450

[0847] Step 1 and step 3 were conducted as essentially as described in the preparation of 232. Step 2 was conducted as essentially as described in the preparation of 426. To a solution of 449-4 (1.0 g, 2.06 mmol) in AcOH (10 mL) was added Fe (576 mg. 10.3 mmol) powder in portions. The mixture was stirred at 80 °C for 2 h. After cooling to r.t, the mixture was neutralized with sat. Na2CC>3 solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous IsASCfi and concentrated under reduced pressure. The residue was purified by column (PE:EA 3:1) to give 449-5 (435 mg. 46.4%). +ESI-MS:m/z 457.0 [M+H]⁺.

[0848] Compound 449-6 was prepared essentially as described in the preparation of 406 by using 449-5 and (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid. Crude 449-6 was purified by prep-HPLC to give 449-6 (92 mg. 40.4%). +ESl-MS:m/z 665.0 [M+H]⁺. Compound 449-6 (92 mg) was separated via SFC separation to give two isomers: 449 (32 mg) and 450 (33 mg). 449; +ESI-MS:m/z 665.0 [M+H]⁺. 450: +ESl-MS:m/z 665.1 [M+H]⁺.

EXAMPLE 234

Preparation of Compound 451

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PCT/US2014/051642 [0849] Compound 451 was prepared essentially as described in the preparation of

443 and 448 by using 451-1. Crude 451 was purified by prep-IIPLC to give 451 as a white solid (42 mg, 16.0%). +ESI-MS:m/z 553.9 [M+H]⁺.

EXAMPLE 235

Preparation of Compound 452

[0850] Compound 452-1 was prepared essentially as described in the preparation of 259. Compound 452-2 was prepared essentially as described in the preparation of 471. Compound 452 was prepared essentially as described in the preparation of 406 by using 4521 and 452-2. Crude 452 was purified by prep-HPLC to give 452 as a white solid (90 mg, 19 %). +ESI-MS:m/z 564.0 [M+H]⁺.

EXAMPLE 236

Preparation of Compound 453

[0851] To a solution of 453-1 (100 mg, 0.493 mmol) in SOCf (3 mL) was added DMF (one drop) at 0 ^l’C. and stirred at r.t. for 1 h. The mixture was co-evaporated with toluene (2x). and re-dissolved in anhydrous DCM (5 mL). The solution was treated with TEA (99.6 mg. 0.986 mol) and 453-3 (164.2 mg. 0.493 mol). The mixture was stirred at r.t. for 1 h. The mixture was diluted with DCM (20 mL) and washed with brine (20 mL). The organic phase was dried over anhydrous NaiSCL and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 453 (42 mg, yield: 16.7%). +ESI-MS:m/z 512.1 [M+H]⁺.

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EXAMPLE 237

Preparation of Compound 454

[0852] Compound 454-2 was prepared essentially as described in the preparation of 406 by using 454-1 and prop-1 -en-2-ylmagnesium bromide. Crude 454-2 was purified by column chromatography (PE:EA 8:1) to give 454-2 as a solid (0.8 g). +ESI-MS:m/z 401.9 [M+H]⁺.

[0853] To a solution of 454-2 (800 mg, 2.0 mmol) in DMSO (10 mL) was added NaNj (650 mg, 10.0 mmol) at r.t.. and the mixture was stirred for 5 h. The reaction w⁷as quenched with water (30 mL). and extracted by EA (3 x 20 mL). The combined organic layers were w⁷ashed with brine, dried over anhydrous NtoSOi and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 6:1) to give 454-3 (402 mg. 55.1%) as a white solid. +ESl-MS:m/z 362.9 [M+H]⁺.

[0854] Ozone w^ras bubbled into a solution of 454-3 (402 mg, 1.1 mmol) in anhydrous methanol (20 mL) at -78 °C for 10 mins. After excess ozone was purged by nitrogen, NaBfL (125 mg, 3.3 mmol) was added. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 454-4 as an oil (303 mg. 74.6%).

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PCT/US2014/051642 [0855] Compound 454 was prepared essentially as described in the preparation of

428 from 454-4 and 454-7. Crude 454 was purified by prep-HPLC to give 454 as a white solid (40 mg, 31.4%). +ESI-MS:m/z 531.0 [M+H]⁺.

EXAMPLE 238

Preparation of Compounds 455, 456, 457 and 458

455455-

essentially as described in PCT [0856] Compound 455-2 was prepared

Publication No. WO 2012/057247, published May 3, 2012, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 455-2. To a solution of 455-2 (2.0 g. 9.17 mmol) in DCM (50 mL) was added DAST (6.0 g, 36 mmol) at 0 °C, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with water (50 mL). The organic layer was washed w ith brine, dried over anhydrous Na₂SO₄ and concentrated under

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PCT/US2014/051642 reduced pressure. The residue was purified by colomn chromatography (PE:EA 100:1) to give 455-3 (1.2 g, 60%).

[0857] To a solution of 455-3 (1.2 g, 5.4 mmol) in anhydrous THF (40 mL) was added /?-BuLi (3 mL. 2.5M in hexane) dropwise at -78 °C. and the solution was stirred for 1 h. 2-isopropoxy-4.4,5.5-tetramethyl-l,3.2-dioxaborolane (1.5 g, 8.1 mmol) was added dropwise, and the mixture was stirred at -78 C for 1 h. The reaction was quenched with water (50 mL). and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by colomn chromatography (PE:EA 100:1) to give 455-4 (0.4 g, 28%).

[0858] Compounds 455-5 to 455-7 was prepared essentially as described in the preparation of 449 by using 455-4. Crude 455-7 w⁷as purified by gel colomn to give 455-7 (0.9 g, 67%). A suspension of 455-7 (1.0 g. 2.9 mmol) and SnC12'2H2O (2.6 g, 12 mmol) in EA (15 mL) was stirred at 70 °C overnight. After cooling to r.t.. ΝΗ3Ή2Ο (5 mL) was added, and the mixture w⁷as stirred for 30 mins. A w⁷hite precipitate w^ras formed and removed by filtration. The filtrate was w⁷ashed with brine, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. Compound 455-8 (0.8 g) was used without further purification.

[0859] Compound 455-9 was prepared essentially as described in the preparation of 406 by using 455-8 and 4-(2-amino-2-oxoethoxy)-3-mcthoxybenzoic acid. Crude 455-9 was purified by prep-HPLC to give 455-9 as a white solid (570 mg, 41%). +ESI-MS:m/z 521.8 [M+H]⁺. Compound 455-9 (570 mg, 1.09 mmol) separated via SFC separation to give two enantiomers: 455-10 (230 mg) and 455-11 (220 mg, 42%).

[0860] To a solution of 455-10 (100 mg, 0.19 mmol) and 455-4 (150 mg, 0.56 mmol) in co-solvent dioxane (4 mL) and H₂O (0.5mL) w⁷ere added Pd(dppf)Cl2 (10 mg. 0.012 mmol) and K2CO3 (55 mg, 0.4 mmol). The mixture w⁷as degassed and then refilled with N2 (3x). The mixture was heated to 150 °C by microwave for 50 mins. The mixture was cooled to r.t., and diluted with EA (30 mL) and water (30 mL). The organic phase w⁷as washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue w⁷as purified by prep-HPLC to give 455-12 as a w⁷hite solid (80 mg, 70%).

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PCT/US2014/051642 [0861] Compound 455-12 (80 mg, 0.15 mmol) was separated via SFC separation to give two isomers: 457 (30 mg) and 458 (29 mg). 457: +ESI-MS:m/z 584.1 [M+H]⁺. 458: +ESI-MS:m/z 584.1 [M+H]⁺.

[0862] Compound 456 was prepared by using 455-11 and 455-4. Crude 456 was purified by prep-HPLC to give 456 as a white solid (75 mg, 65%). +EST-MS:m/z 584.1 [M+H]⁺. Compound 455 was prepared by using 455-9 and 455-4. Crude 455 was purified by prep-HPLC to give 455 as a white solid (40 mg. 23.3%). +ESI-MS:m/z 584.1 [M+H]⁺.

EXAMPLE 239

Preparation of Compound 459

[0863] Compound 459-2 w⁷as prepared essentially as described in Hay et al., J. Med. Chem. (2010) 53(2):787-797. which is hereby incorporated by reference for the limited purpose of its description of the preparation of 459-2. Compound 459-3 was prepared essentially as described in PCT Publication No. WO 2012/020786, published Feb. 16, 2012, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 459-3.

[0864] To a solution of NaBH₄ (60 mg. 1.58 mmol) in a mixture of THE (5 mL) and MeOH (1 mL) w⁷as added 459-3 (150 mg, 0.794 mol) in portions. The mixture was stirred at r.t. for 1 h. The reaction was quenched with water (10 mL), and extracted with EA (3x10 mL). The combined organic phase was washed with brine, dried over anhydrous NajSOi and concentrated under reduced pressure. The residue was purified by colomn chromatography (10-20% EA in PE) to give 459-4 (97 mg. 63.8 %).

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PCT/US2014/051642 [0865] To a solution of 459-4 (573 mg, 3.0 mmol), isoindoline-1,3-dione (441 mg, 3.0 mmol) and PPh₃ (943 mg, 3.0 mmol) in anhydrous TIIF (15 mL) was added DIAD (727 mg, 3.0 mmol) dropwise at 0 °C under N?. The mixture was stirred for 2 h at r.t. The reaction was quenched by sat. NaHCO₃ solution (30 mL). The mixture was extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine, dried over anhydrous MgSCfl and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 459-5 (604 mg, 62.9%).

[0866] Compounds 459-5 to 459-12 was prepared essentially as described in the preparation of 428. Crude 459-12 was purified by flash column chromatography (10-20% EA in PE) to give 459-12 (127 mg, 65.8%). A suspension of 459-12 (127 mg, 0.326 mmol) in N2H4TLO (10 mL) was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 459 (35 mg, 33.9%). +ES1MS:m/z 568.0 [M+H]⁺.

EXAMPLE 240

Preparation of Compound 460

[0867] Compounds 460-1 to 460-6 were prepared essentially as described in the preparation of 272 and 403. Crude 460-6 was purified by prep-HPLC to give 460-6 as a white solid (67 mg, 50%). To a solution of 460-6 (100 mg, 0.16 mmol) in DCM (5mL) was

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PCT/US2014/051642 added TFA (1 mL). The mixture was stirred at r.t. for 1 h. and then concentrated under reduced pressure. The residue was purified by prep-11PLC to give 460 (30 mg, 60%). +ESIMS:m/z 528.1 [M+H]⁺.

EXAMPLE 241

Preparation of Compound 461

[0868] Compound 461-2 was prepared essentially as described in PCT Publication No. WO 2013/055645, published April 18, 2013, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 461-2. Compound 461-3 was prepared essentially as described in Podlech et al., Helv. Chimica Acta (1995) 78(5):1238-1246, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 461-3. Compound 461-4 was prepared essentially as described in PCT Publication No. WO 2009/154780, published Dec. 23, 2009, which is

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PCT/US2014/051642 hereby incorporated by reference for the limited purpose of its description of the preparation of461-4.

[0869] To a solution of 461-4 (9.0 g, 39.3 mmol) in anhydrous DMF (t>0 mL) were added DIPEA (15.2 g. 117.9 mmol) and HATU (14.9 g, 39.3 mmol), and the mixture was stirred at r.t. for 30 mins. Ν,Ο-dimethylhydroxylamine (3.85 g, 39.3 mmol) was added, and the mixture was stirred at r.t. for 2 h. The mixture was diluted with water (100 mL), and extracted with EA (3 x 100 mL). The combined organic phase was washed brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 461-5 (8.5 g, 70.7%).

[0870] To a solution of 461-5 (8.0 g, 31.0 mmol) and 2-bromo-6-iodo-3methoxypyridine (9.7 g, 31.0 mmol) in anhydrous THF (120 mL) was added i-PrMgCl (23.5 mL, 46.51 mmol) dropwise at 0 °C, and the mixture was stirred at r.t. for 2 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 150 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 8:1) to give 461-6 (6.0 g, 49.6 %). +ESI-MS:m/z 385.01 [M+H]⁺.

[0871] Compound 461-7 was prepared as essentially as described in the preparation of 428 by using 461-6. Compound 461-7 (4.2 g) was obtained after purification by column chromatography.

[0872] To a suspension of CH₃P⁺Ph3Br‘ (2.46 g, 6.92 mmol) in toluene (20 mL) was added NaHMDS (6.92 mL, 1 M in THF) dropwise at 0 ^UC under N2. The mixture was stirred for 30 mins. The mixture was cooled to -78 °C and 461-7 (2.0 g. 4.6 mmol) was added, and then stirred at -78 °C to reflux overnight. The reaction was quenched by water (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 461-8 (1.2 g, 61.0%).

[0873] To a solution of 461-8 (1.3 g, 3.0 mmol) in DCM (20 mL) were added NMO (1.05 g. 9.0 mmol) and OsOq (38.4 mg, 0.15 mmol), and the mixture was stirred at r.t. overnight. The reaction was quenched with sat. Na₂SO₃ solution (50 mL) and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous

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Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 3:1) to give 461-9 (0.85 g, 60.7%).

[0874] To an ice-cold solution of 461-9 (265 mg, 0.725 mmol) and TEA (220 mg, 2.2 mmol) in anhydrous DCM (20 mL) was added MsCl (1.0 g. 8.7 mmol) dropwise, and the mixture was stirred at r.t. for 1 h. The mixture was washed with brine (20 mL). dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 461-10 (250 mg, 63.4%).

[0875] Compound 461 was prepared essentially as described in the preparation of 428 from 461-10. Crude 461 was purified by prep-HPLC to give 461 as a white solid (36 mg. 20.2%). +F,SI-MS:tn/z 556.1 [M+H]⁺.

EXAMPLE 242

Preparation of Compound 462

[0876] To a solution of 462-1 (3.56 g, 10.0 mmol) in DMSO (30 mL) was added

NaN₃ (1.95 g, 30.0 mmol) at 25 °C in portions, and the mixture was stirred for 30 mins. The mixture was poured into water (50 mL), and extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 462-2 (2.4 g. 75.1%) as a white solid. +ESI-MS:m/z 320.9 [M+H]⁺.

[0877] To a solution of 462-2 (2.4 g, 7.5 mmol) in anhydrous THF (30 mL) was added vinyl-magnesium bromide (7.5 mL, 1.0M in THF) dropwise at -30 °C under N₂, and

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PCT/US2014/051642 the mixture was stirred for 30 mins. The reaction was quenched with sat. NH4CI solution (50 mL). The mixture was allowed to warm to r.t. and extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 462-3 as a white solid (2.0 g. 76.9%). +ESI-MS:m/z 349.0 [M+H]⁺.

[0878] Ozone was bubbled into a solution of 462-3 (2.0 g, 5.7 mmol) in anhydrous MeOH (20 mL) at -78 °C for 10 mins. After excess Ozone was purged by N₂. NaBH₄ (800 mg, 21.1 mmol) was added at r.t. in portions. The mixture w^ras stirred at r.t. for 30 mins. The reaction was quenched with waler (30 mL) and extracted with EA (2 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1:1) to give 462-4 as an oil (1.6 g, 80.1%). +ESl-MS:m/z 352.9 [M+H]⁺.

|0879] To a solution of 462-4 (1.6 g. 4.5 mmol) and TEA (900 mg, 8.9 mmol) in anhydrous DCM (20 mL) was added MsCl (500 mg. 4.4 mmol) dropwise at 0 °C. The solution was stirred at r.t. for 30 mins. The reaction was quenched with H₂O (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 4:1) to give 462-5 as a solid (1.6 g. 84.2%). +ESIMS:m/z431 [M+H]⁺.

[0880] To a solution of 462-5 (1.6 g. 3.7 mmol) in CH₂,CN (20 mL) was added azetidine hydrochloride (1.6 g, 17.2 mmol) at r.t. The solution w^ras heated to 70 °C and stirred for 8 h. After cooling to r.t., the reaction was quenched with H₂O (30 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1:1) to give 462-6 as an oil (500 mg, 35.7%). +ESIMS:m/z 391.9 [M+H]⁺.

[0881] Compound 462 was prepared essentially as described in the preparation of 428 by using 462-6. Crude 462 w'as purified by prep-HPLC to give 462 as a w'hite solid (10 mg, 6.5%). +ESl-MS;m/z 556.1 [M+H]⁺.

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EXAMPLE 243

Preparation of Compound 463

[0882] Compound 463 was prepared essentially as described in the preparation of

461 by using 1 -(tcrt-butoxycarbonyl)azetidinc-3-carboxylic acid.

Compound 463 was obtained as white solid (40 mg. 40%). +EST-MS:m/z 542.1 [M+H]⁺.

EXAMPLE 244

Preparation of Compound 464

COOH COOMe COOMe COOMe

464-1 464-2 464-3 464-4

L/UOivie vie

464-5 464-6

[0883] Compound 464-2 was prepared essentially as described in Zornik et al.. Chem. Eur. J. (2011) 17(5):1473-1484 and S1473/1-S1473/121, which is hereby incorporated by reference for the limited purpose of its description of the preparation of 464-2. Compound 464-10 was prepared essentially as described in the preparation of 272 by using 464-2. Compound 464-10 was obtained as white solid (300 mg, 68.5%). +ESI-MS:m/z 582.9 [M+H]⁺.

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PCT/US2014/051642 [0884] To a solution of 464-10 (50 mg, 0.086 mmol) in 1.4-dioxane (5 mL) was added ammonia water (2 mL) in a sealed tube. The mixture was then stirred at 100 °C overnight. After cooling to r.t., tire mixture was concentrated to dryness, and the residue was purified by prep-HPLC to give 464 (15 mg, 30.8%) as a white solid. +ESI-MS:m/z 568.0 [M+H]⁺.

EXAMPLE 245

Preparation of Compound 465

[0885] To a stirred solution of 465-1 (87.3 mg, 0.15 mmol) in THF (5 mL) at 0°C was added LAH (5.7 mg. 0.15 mmol) under N?. After stirring at 0 °C for 1 h, the reaction was quenched by water (10 mL). and extracted by EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated to dryness. The residue was purified by prep-HPLC to give 465 (50 mg, 60.2%) as a white solid. +ESIMS:m/z 555.0 [M+H]⁺.

EXAMPLE 246

Preparation of Compound 466

H [0886] Compound 466 was prepared essentially as described in the preparation of

459 by using l-(2,6-dichloropyridin-4-yl)ethanone. Compound 466 was obtained as white solid (20 mg, 18.5 %). +ESl-MS:m/z 582.1 [M+H]⁺.

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EXAMPLE 247

Preparation of Compound 467

[0887] To a solution of 467-1 (60 mg, 0.12 mmol) in THF (4 mL) was added MeMgCl (1 mL, 3 M in ether) dropwise at 0 C, and the mixture was stirred at for 1 h. The reaction was quenched with sat. NH₄C1 solution, and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous NaqSOq and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 467 (30 mg. 47%) as a white solid. +ESI-MS:m/z 531.3 [M+H]⁺.

EXAMPLE 248

Preparation of Compound 468

10888] To a solution of 468-1 (2.4 g, 20 mmol) in anhydrous THF (50mL) was added n-BuLi (8 mL. 2.5M in hexane) at -78 °C under N₂. and the mixture was stirred for 0.5 h. The mixture was treated with tributylchlorostannane (6.5 g. 20 mmol) in portions, and stirred at -78 °C for 1 h. The reaction was quenched by water (50 111L), and extracted with EA (3x 50 mL). The combined organic phase was washed with brine, dried over anhydrous NajSiL and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:1) to give 468-2 (6 g, 74 %).

[0889] A mixture of 468-2 (2.02 g. 5.0 mmol). Pd(dppf)Cl₂ (90 mg. 2% eq.) and l-(6-bromo-5-methoxypyridin-2-yl)-2.2,2-trifluoroethanone (1.5 g, 5mL) was dissolved in dry DMF (10 mL) under N₂. The mixture was heated to 130 °C by microwave and stirred for

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0.5 h. After cooling to r.t., the mixture was poured into water (50 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous

LaoSOi and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 5:1) to give 468-3 (1.4 g, 82 %).

[0890] Compound 468 was prepared essentially as described in the preparation of 424 by using 468-3. Crude 468 was purified by pre-HPLC to give 468 as a white solid (50 mg, 20 %). +ESI-MS:m/z 547.9 [M+H]⁺.

EXAMPLE 249

Preparation of Compound 469 o'

[0891] Compound 469 was prepared according to the method described in the preparation of 176. LCMS: m/z 553.10 [M+H]⁺.

EXAMPLE 250

Preparation of Compound 135

F

[0892] Compound 135-2 was prepared essentially as described in Granzhan et al..

Angew. Chem. Int'l Ed. (2010) 49(32): 5515-5518, S5515/1-S5515/30. which is hereby

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PCT/US2014/051642 incorporated by reference for the limited purpose of its description of the preparation of 1352.

[0893] To a solution of 135-2 (10.0 g, 57.8 mmol) in anhydrous THF (60 mL) was added zv-BuLi (35 mL, 2.5 M in hexane) dropwise at -78 °C under N₂. The mixture was stirred at -78 °C for 30 mins, under N₂ and oxirane (15.5 mL. 289 mmol) was added. The mixture was warmed to r.t. and stirred for 2 h. The reaction was quenched with H₂O, and extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 3:1) to give 135-3 (3.5 g, 28%). +ESI-MS:m/z 217.9 [M+H]⁺.

[0894] To a solution of 135-3 (3.5 g, 16.1 mmol) in MeOH (60 mL) was added cone. HC1 solution (15 mL, 12 N) at r.t., and stirred at 60 °C for 5 h. The reaction was quenched with sat. NaHCCf solution, and extracted with EA (3 x 50 mL). The combined organic phase w^ras washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1:1) to give 135-4 (1.02 g, 36%).

[0895] To a solution ol'135-4 (1.02 g, 5.7 mmol) and K₂CO₂ (1.5 g, 11.5 mmol) in a mixture of THF (10 mL) and H₂O (10 mL) was added I₂ (1.5 g, 6.0 mmol) in portions, and the mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaS₂O₂solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 2:1) to give 135-5 (1.1 g. 62.5%).

[0896] To a solution of 135-5 (1.1 g. 3.7 mmol) and PPI13 (1.5 g. 5.7 mmol) in anhydrous THF (10 mL) was added DIAD (1.2 g, 5.7 mmol) at r.t. under N₂. The mixture was heated to 70 °C for 1 h and then cooled to r.t. The reaction was quenched with H₂O, and extracted with EA (3 x 30 ml.). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 2:1) to give 135-6 (0.8 g, 78%). +ESI-MS:m/z 281.8 [M+H]⁺.

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PCT/US2014/051642 [0897] To a solution of 135-6 (0.8 g, 7.1 mmol) and 135-7 (2.2 g, 7.1 mmol) in TIIF (10 mL) was added i-PrMgBr (21mL, LO M in THF) dropwise under N₂, and the mixture was stirred at r.t. for 1 h. The reaction was quenched with sat. NH₄C1 solution and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 1:1) to give 135-8 (1.2 g, 77%). +EST-MS:m/z 408.9 [M+H]⁺.

[0898] To a solution of 135-8 (408 mg, 1.0 mmol), (3-chloro-4fluorophenyl)boronic acid (175 mg, 1.0 mmol) and CS2CO3 (276 mg, 2.0 mmol) in dioxane (5 mL) and w⁷ater (1 mL) w⁷as added Pd(dppf)Cl₂ (82 mg, 0.1 mmol) under N₂. The mixture was heated to 120 °C under microwave irradiation and stirred for 30 mins. The mixture was cooled to r.t., poured into cold H₂O and extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 135 (80 mg) as a w⁷hite solid. +ESl-MS:m/z 502.9 [M+H]⁺.

EXAMPLE 251

Preparation of Compound 470

[0899] To a solution of 470-1 (1.7 g, 6.7 mmol) in DCM (10 mL) was added DAST (3 mL) at 0 °C, and the mixture w^ras stirred at 0°C for 30 mins. The resulting was quenched with sat. NaHCO₃ solution at 0 °C and extracted by EA (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 15:1) to give 470-2 as a white solid (800 mg. 47.1%).

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PCT/US2014/051642 [0900] To a solution of 470-2 (254 mg, 1.0 mmol) in MeOH (5 mL) was added

NaOI 1 (5 mL, 2/V), and the mixture was stirred at reflux for 1 h. The mixture was cooled to

r.t. and acidified to pH 4~5 using HCI (2 M). The mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous lASCf and concentrated under reduced pressure to give 470-3 as a Lkc solid (100 mg, 4 I .tri□).

[0901] To a solution of 470-3 (100 mg, 0.42 mmol), HATU (190 mg, 0.5 mmol) and DIPEA (129 mg. 1.0 mmol) in anhydrous DCM (5 mL) was added 470-4 (140 mg, 0.39 mmol) at 25 °C. The solution was stirred for 1 h and then quenched with aq. NaHCCfi solution. The aqueous phase was extracted with DCM (2 x 10 mL). The combined organic phase was washed with brine, dried over anhydrous JASCfi and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 470 as a white solid (60 mg. 24.5¾). +ESI-MS:m/z 586.9 [M+H]⁺.

EXAMPLE 252

Preparation of Compound 471

[0902] To a solution of bromide 471-1 (5.0 g. 28.9 mmol) and (3-chloro-4 fluorophenyl)boronic acid (5.5 g, 31.8 mmol) in dioxane (50 mL) were added Pd(dppf)CL (816 mg, 1.0 mmol) and a freshly prepared CS2CO3 solution (11 g in 50 mL of water) under N2. The mixture was stirred at 70 °C for 3 h. The solution was cooled to r.t.. poured into ice water and extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous NaoSCf and concentrated under reduced pressure. The residue

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PCT/US2014/051642 was purified by column chromatography (PE:EA 10:15:1) to give 471-2 (5.5 g) as a white solid.

[0903] To a solution of 471-2 (3.9 g, 17.4 mmol) and IC2CO3 (3.0 g, 21.7 mmol) in DMF (50 mL) was added E (1.4 g, 5.5 mmol) in portions at r.t., and the mixture was stirred for 2 h. The reaction was quenched with sat. NajSiOj solution, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhyrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 50:1—25:1) to give 471-3 as a white solid (2.1g, 50%). +ESIMS:m/z 349.8 [M+H]⁺.

[0904] To a solution of 471-3 (2.0 g, 5.7 mmol) and K2CO3 (790 mg. 5.7 mmol) in DMF (25 mL) was added Mel (1.5 g, 11 mmol) dropwise at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with water, and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhyrous NivSOi and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 50:1) to give 471-4 as a white solid (1.lg. 55%).

[0905] To a solution of 471-4 (1.1 g, 3.0 mmol), picolinic acid hydrochloride (240 mg, 1.5 mmol), C.S2CO3 (2.8 g, 8.7 mmol) and Cui (165 mg, 0.75 mmol) in DMF (20 mL) was added ethyl 2-cyanoacetate (650 mg, 6.0 mmol) under N₂. The mixture was heated to 130 °C under microwave irradiation and stirred for 30 mins. The mixture was cooled to r.t., poured into water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous \a2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 10:15:1) to give 471-5 as a yellow solid (720 mg, 65%). +ESI-MS:m/z 348.8 [M+H]⁺.

[0906] To a solution of 471-5 (720 mg. 2.04 mmol) in anhydrous DMF (15 mL) was added NaH (130 mg. 3.12 mmol) in portions at 0 °C. After stirring for 30 mins.. Mel (840 mg, 6 mmol) was added. The mixture was stirred at 0 °C for 2 h. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous Xa₂SO| and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA 25:1) to give 471-6 as a white solid (468 mg, 65%). +ESl-MS:m/z 362.8 [M+H]⁺.

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PCT/US2014/051642 [0907] To a solution of 471-6 (460 mg, 1.27 mmol) in anhydrous THF (15 mL) was added LAI1 (250 mg, 5 mmol) at 0 °C under N₂, and the mixture stirred at 0 °C for 2 h. The reaction was quenched with water, and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhyrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by prep-TLC to give 471-7 (150 mg. 36%). +ESI-MS:m/z 324.8 [M+H]⁺.

[0908] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (60 mg, 0.3 mmol), HATU (70 mg. 0.5 mmol) and D1EA (300 mg. 0.7 mmol) in DCM (15 mL) was added amine 471-7 (100 mg. 0.3 mmol). After stirring at r.t. for 30 mins., the reaction was quenched with sat. NaHCCh solution, and extracted with DCM (3x10 mL). The combined organic phase was washed with brine, dried over anhyrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 471 as a white solid (55 mg, 32%). +ESI-MS:m/z 519.0 [M+H]⁺.

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EXAMPLE 253

Preparation of Compounds 509-513

[0909] Potassium carbonate (29.8 g, 216 mmol) and trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) were sequentially added to a suspension of 509-1 (14.0 g, 108 mmol) in water (210 mL). The reaction was stirred at 100 °C overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) was added. The reaction was stirred at 100 °C for 7 h, and further trifluoroacetaldehyde ethyl hemiacetal (19 mL, 162 mmol) was added. After 16 h at 100 °C, the reaction was cooled to 0 °C. neutralized with IM aq. HCI solution and extracted with EtOAc. The organic portion was dried with Ua₂SO|. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 70:30) afforded 509-2 (24.0 g, 80% purity A/A UV).

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PCT/US2014/051642 [0910] Iodine (40.1 g. 158 mmol) was added to a solution of 509-2 (24.0 g) and potassium carbonate (28.9 g, 210 mmol) in water (350 mL). The mixture was stirred at r.t. overnight. A IM aq. sodium thiosulfate solution was added. The mixture was treated with 3N aq. HCI until a white solid formed. EtOAc was added and the layers were separated. The aqueous phase was extracted with EtOAc (3x). The combined organic portions were dried with \a₂SO| and fdtered. The solvents were removed under reduced pressure. Chromatography of the residue (cyclohexaneiEtOAc, 100:0 to 70:30) afforded 509-3 as a white solid (21.0 g, 50% over two steps). UPLC/MS(ES⁺) m/z: 354.03 [M+H]⁺.

[0911] Chloroacetone (2.6 mL, 32.8 mmol) was added to a solution of 509-3 (10.5 g, 29.8 mmol) and potassium carbonate (6.18 g. 44.8 mmol) in acetone (170 mL). The reaction was stirred at 50 °C overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic portion was dried with NasSOa. filtered and concentrated under reduced pressure. The residue w⁷as tritrated with DCM. and the precipitate dried to afford 509-4 as a white solid (6.80 g, 55%). UPLC/MS(ES⁺) m/z: 409.92 [M+H]⁺. The supernatant was concentrated under reduced pressure, and the residue chromatographed (cyclohexane:EtOAc, 100:0 to 0:100) to afford unreacted 509-3 (1.20 g, 11%).

[0912] The reaction was performed in 8 batches. A mixture of 509-4 (841 mg, 2.05 mmol), 2-methylpropane-2-sulfinamide (273 mg, 2.26 mmol) and titanium(IV) ethoxide (1.03 g, 4.51 mmol) in THF (16 mL) was heated to 70 °C (sealed vial, degassed and purged with N₂). The mixture was stirred at 70 °C for 3 h. The 8 batches were unified. EtOAc and water were added. The mixture was stirred for 5 mins, and then filtered through a pad of celite. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO4 and filtered. The volatiles w⁷ere removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50 to 0:100) afforded 509-5 (5.36 g, 63%). UPLC/MS(ES⁺): m/z 513.10 [M+H]⁺.

10913] w-Buthyllithium (1.6M solution in THF, 6.60 mL, 10.5 mmol) was added to a solution of EtMgBr (TM in THF, 5.23 mL, 5.23 mmol) in THF (15 mL). which had been pre-cooled to 0°C. After 10 mins, the mixture w⁷as cooled to -78 °C. A solution of 509-5 (2.68 g, 5.23 mmol) in THF (15 mL) w⁷as added dropwise. The reaction was stirred at -78°C

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PCT/US2014/051642 for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with brine, and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na^SO-i. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 5096 as a yellow wax (2.60 g, 64%).

[0914] Dess-Martin periodinane (3.14 g, 7.46 mmol) was added to a stirred solution of 509-6 (2.60 g. 6.73 mmol) in DCM (36 mL). The reaction was stirred at r.t. under N? atmosphere for 3 h. The reaction was quenched with a 1:1 mixture of 2M aq. Na2S₂O₃and sat. aq. NaHCO₃. After 30 mins of vigorous stirring, the layers w^rere separated. The organic portion was washed with brine, dried with Na2SC>4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexaneiEtOAc, 100:0 to 50:50) afforded 509-7 as a while solid (2.11 g, 81%). UPLC/MS(ES⁺): m/z 385.16 [M+H]⁺, 403.18 [M+H3O]⁺.

|0915] The reaction was performed in 2 batches. Trimethylsulfoxonium iodide (601 mg, 2.73 mmol) was added in 1 portion to a mixture of tBuOK (305 mg, 2.73 mmol) in CH₃CN (50 mL), which had been previously degassed. The mixture was further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution of 509-7 (1.05 g, 2.73 mmol) in CH₃CN (50 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The 2 batches were combined, and the volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexanerEtOAc. 100:0 to 50:50) afforded 509-8 as a colorless wax (1.45 g, 66%). UPLC/MS(ES⁺): m/z 399.14 [M+H]⁺.

[0916] A solution of 509-8 (1.45 g. 3.64 mmol) in 7M NH₃-MeOH (800 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford 509-9 (1.43 g), which was used in the next step.

[0917] Method A: A mixture of 509-9 (750 mg). EDC (448 mg. 2.35 mmol), HOBT (317 mg. 2.35 mmol), TEA (500 uL. 3.60 mmol) and acid (1.80 mmol) in DCM (18 mL) was stirred at r.t. for 2 h. Water was added, and the mixture was stirred for 10 mins. The layers were separated, and the organic portion was dried with Na₂SC>4. The solvent was

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PCT/US2014/051642 evaporated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 509-10.

[0918] Method B: A solution of acid (0.120 mmol), HATU (44 mg) and DIPEA (110 uL) in DMF or DCM (1 mL) was stirred at r.t. for 15 mins. A solution of 509-9 (50 mg) in DMF (or DCM. 1 mL) was added to the reaction. The mixture was stirred at r.t. for 20 mins. The majority of the volatiles were removed under reduced pressure. The residue was taken up with EtOAc, and the organic portion was washed with 1M aq. NaOH and 1M aq. HCI, dried with MoSCL. filtered and concentrated under reduced pressure to give 509-10.

[0919] A mixture of 509-10 (0.582 mmol), boronic acid (0.872 mmol), K3PO4 (247 mg. 1.16 mmol). KH2PO4 (158 mg, 1.16 mmol) and PdfobpfjCL (13.8 mg, 0.029 mmol) in a DME;EtOH:H2O mixture (5:3:1, 9 mL) was degassed and warmed to 50 °C for 6 h. DCM and water were added. The layers were separated, and the organic portion was dried with MbSCf. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 509-11.

[0920] A 4M HCl-dioxane solution (1 mL) was added to a solution of 509-11 (0.508 mmol) in MeOH (5 mL). After 15 mins, the volatiles were removed under reduced pressure. The residue was dissolved in DCM. The organic portion was washed with 5% aq. NaHCOj solution and water, dried with Na₂SO4, filtered and concentrated under reduced pressure to afford 509-12.

[0921] Coupling of 509-9 with 4-cyclopropoxy-3-methoxybenzoic acid according to Method A afforded 509-10A as a white solid (85%). UPLC/MS(ES⁺): m/z 606.24

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PCT/US2014/051642 [M+H]⁺. Suzuki coupling of 509-10A with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis afforded 509 as a white solid (53% over two steps). UPLC/MS(ES⁺):

m/z 562.20 [M+H]⁺.

[0922] 509 (53 mg) was dissolved in DCM. The solution was washed with sat.

aq. NaHCOs solution, dried with Na2SO₄, filtered and concentrated under reduced pressure. The amine was resolved by prep-HPLC [Chiralpak AD-H (25 x 3 cm, 5 um), mobile phase: n-hexane/(ethanol+0.1% ipa) 80:20 % v/v. flow rate: 32mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: a mixture of 510, 512 and 513: tR= 21.0 min: and 511: white solid (7.3 mg, tR= 28.5 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

[0923] The mixture of 510, 512 and 513 was resolved by prep-HPLC [Chiralpak 1C (25 x 3 cm, 5 um), mobile phase: n-hexane/(ethanol + 0.1% ipa) 70/30 % v/v, flow rate: 32 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: a mixture of 512 and 513: t_R= 8.2 min; and 510: white solid (7.1 mg. tR= 10.6 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

[0924] The mixture of 512 and 513 was resolved by prep-HPLC [Chiralpak OJ-H (25 x 3 cm, 5 um). mobile phase: n-hexane/(ethanol/MeOH 1/1 + 0.1% ipa) 65/35 % v/v, flow rate: 38 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: 512: white solid (6.0 mg, t_R= 7.2 min). IJPLC/MS(ES⁺): m/z 562.20 [M+I1]⁺; and 513: white solid (6.0 mg, tR= 11.3 min). UPLC/MS(ES^H): m/z 562.20 [M+II] .

[0925] Alternatively, 509 (220 mg) was resolved by prep-HPLC [Chiralpak IC (25 x 2 cm. 5 um). mobile phase: n-hexane/(ethanol/methanol 1/1 +0.1% ipa) 86/14% v/v. flow rate: 16 mL/min. UV detection DAD 220 nm]. Three fractions were recovered based on retention times: a mixture of 512 and 513: (104 mg. t_R= 13.4 min); 511: (40 mg. 14%, tR= 15.0 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺; and 510: (35 mg. 12%, t_R= 17.5 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

[0926] The mixture of 512 and 513: was resolved by prep-HPLC [Chiralcel OJ-H (25 x 3 cm, 5 um). mobile phase: n-hexane/(ethanol/methanol 1/1 +0.1% ipa) 65/35% v/v. flow rate: 40 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on

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PCT/US2014/051642 retention times: 512 (41 mg, 14%, t_R= 7.5 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺; and

513 (46.6 mg, 16%, t_R= 12.0 min). UPLC/MS(ES⁺): m/z 562.20 [M+H]⁺.

EXAMPLE 254

Preparation of Compound 542

[0927] Suzuki coupling of 509-10A with 4-cyanophenylboronic acid followed by hydrolysis of the resulting sulfmamide afforded 542 (78% over 2 steps). UPLC/MS(ES⁺): m/z 569.40 [M+H]^d.

EXAMPLE 255

Preparation of Compound 539

[0928] Coupling of 509-9 (50 mg) with 4-(2-(4-methoxybenzyloxy)ethoxy)-3methoxybenzoic acid according to Method B afforded 509-10B. Suzuki coupling of 509-10B with 4-fluorophenylboronic acid followed by sulfmamide hydrolysis and PMB-group removal afforded 539 as an off-white solid (10 mg). UPLC/MS(ES'): m/z 566.30 [M+H]⁺.

EXAMPLE 256

Preparation of Compound 543

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PCT/US2014/051642 [0929] Coupling of 509-9 (80 mg) with 4-(carbamoylmethoxy)-3-methoxybenzoic acid according to Method B afforded 509-10 C. Suzuki coupling of 509-10C with 4fluorophenylboronic acid followed by sulfinamide hydrolysis afforded 543 as an off-white solid (8.7 mg). UPLC/MS(ES⁺): m/z 579.40 [M+H]⁺.

EXAMPLE 257

Preparation of Compound 556

[0930] Coupling of 509-9 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method A afforded 509-10D. UPLC/MS(ES⁺): m/z 624.20 [M+H]⁺. Suzuki coupling of 509-10D with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis afforded 556 as an off-white solid (50% over 2 steps). UPLC/MS(ES⁺): m/z 580.33 [M+H]⁺.

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EXAMPLE 258

Preparation of Compounds 494, 498, 482 and 483

494-14

[0931] A mixture of 509-2 (5.00 g, 22.0 mmol). (3-chloro-4-fluorophenyl)boronic acid (7.66 g. 44.0 mmol), Pd(dppf)C12 (1.60 g, 2.20 mmol) and Na₂CO₃ (2M aq solution. 22.0 mL, 44.0 mmol) in DCE (250 mL) was degassed and heated to reflux for 16 h. Additional Pd(dppf)Cl₂ (0.05 eq), (3-chloro-4-fluorophenyl)boronic acid (1 eq.) and aq Na₂CO₃ (1 eq) were added. The reaction was refluxed for 4 h and then water was added. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:DCM. 70:30 to 0:100) afforded 49413 as a yellow solid (2.74 g). IJPLC/MS(ES⁺): m/z 322.10 [M+H]⁺.

[0932] Iodine (1.77 g. 6.98 mmol) was added to a solution of 494-13 (2.24 g. 6.98 mmol) and potassium carbonate (2.89 g, 20.9 mmol) in water (100 mL). The mixture was

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PCT/US2014/051642 stirred at r.t. for 30 mins. A 1M aq. sodium thiosulfate solution was added. The mixture was treated with 3N aq. HCI until a white solid formed. EtOAc was added, and the layers were separated. The aqueous phase was extracted with EtOAc. The combined organic portions were dried with Na₂SO₄ and filtered. The solvents were removed under reduced pressure. Chromatography of the residue (cvclohexane:EtOAc. 100:0 to 80:20) afforded 494-14 as a light yellow solid (2.80 g, 90%). UPLC/MS(ES⁺): m/z 448.05 [M+H]⁺.

[0933] Chloroacetone (548 pL. 6.89 mmol) was added to a solution of 494-14 (2.80 g. 6.26 mmol) and potassium carbonate (1.30 g, 9.40 mmol) in acetone (40 mL). The reaction was stirred at 50 °C for 24 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic portion was dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexaneDCM, 60:40 to 30:70) afforded 494-15 as a white solid (2.38 g. 75%). UPLC/MS(ES⁺): m/z 504.27 [M+H]⁺.

10934] A mixture of 494-15 (1.87 g. 3.72 mmol). 2-methylpropane-2-sulfinamide (495 mg, 4.09 mmol) and titanium(IV) ethoxide (1.86 g. 8.18 mmol) in THF (30 mL) was heated to 70 °C (sealed vial, degassed and purged with N₂). The mixture was stirred at 70 °C overnight. EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated, and the organic portion was dried with Na₂SO4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 20:80) afforded 494-16 as a light yellow solid (1.00 g, 45%). UPLC/MS(ES⁺): m/z 607.07 [M+H]⁺.

[0935] w-Buthyllithium (1.6 M solution in THF. 2.07 mL, 3.32 mmol) was added to a solution ofEtMgBr (1 M solution in THF, 1.66 mL, 1.66 mmol) in THF (5 mL), which had been pre-cooled to 0°C. After 10 mins, the mixture was cooled to -78°C. A solution of 494-16 (1.00 g, 1.66 mmol) in THF (5 mL) was added dropwise, and the reaction was stirred at -78 °C for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with brine, and the aqueous portion extracted with EtOAc. The combined organic portions w'ere dried with Na₂SO4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50 to 0:100) afforded 49417 (775 mg, 70% purity A/A UV).

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PCT/US2014/051642 [0936] Dess-Martin periodinane (822 mg, 1.94 mmol) was added to a stirred solution of 494-17 (775 mg) in DCM (7mL). The reaction was stirred at r.t. for 2 h and quenched with a 1:1 mixture of 2M aq. NaiSoOa and sat. aq. NaHCO.3. After 20 mins of vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na2SO.|. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50 to 0:100) afforded 494-18 (480 mg, 60% over 2 steps).

[0937] Trimethylsulfoxonium iodide (57.5 mg. 0.261 mmol) was added in one portion to a mixture of tBuOK (29.2 mg, 0.261 mmol) in CH₃CN (5 mL), which had been previously degassed. The mixture was further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 494-18 (125 mg. 0.261 mmol) in CH3CN (4 mL), which had been previously degassed. The reaction was stirred at r.t. for 15 mins. The volatiles were removed under reduced pressure. Chromatography of the residue (cvclohexane:EtOAc, 80:20 to 0:100) afforded 494-19 as a colorless wax (51 mg, 40%). UPLC/MS(ES⁺): m/z 493.20 [M+H]⁺.

[0938] A solution of 494-19 (51 mg) in 7M NEf-MeOH (30 mL) was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure to afford 494-20 (62 mg), which was directly in the next step.

[0939] A mixture of acid (0.136 mmol), HATU (51.7 mg, 0.136 mmol) and DIPEA (43 uL, 0.246 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. A solution of 494-20 (62 mg) in DCM (2 mL) was added, and the mixture was stirred at r.t. for 1 h. The reaction was partitioned between DCM and water, and the layers were separated. The organic portion was washed with brine, dried with Na^SCq. filtered and concentrated under reduced pressure. Chromatography of the residue afforded 494-21.

[0940] A 4M HCl-dioxane solution (1 mL) was added to a solution of 494-21 (0.060 mmol) in MeOH (5 mL). After 30 mins, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 494-22.

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[0941] Coupling of 494-20 with 3-chloro-4-ethoxybenzoic acid followed by hydrolysis of the resulting sulfinamide afforded 494 (42% over 3 steps). UPLC/MS(ES⁺): m/z 588.20 [M+H]⁺.

OMe

O

498c

OMe

[0942] Coupling of 494-20 with 4-ethoxy-3-methoxybenzoic acid followed by hydrolysis of the resulting sulfinamide afforded 498 (28% over three steps). UPLC/MS(ES⁺): m/z 584.30 [M+H]⁺.

[0943] Coupling of 494-19 with 4-cyclopropoxy-3-methoxybenzoic acid afforded

482 (68% over 2 steps). UPLC/MS(ES⁺): m/z 700.32 [M+H]⁺.

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[0944] Hydrolysis of 482 according to general procedure afforded 483 as a white solid (formic acid salt, 76%). Alternatively. 483 was prepared by Suzuki coupling of 50910A with 3-chloro-4-fluorophenylboronic acid and subsequent hydrolysis of the resulting suliinamide (53% over 2 steps). UPLC/MS(ES⁺): m/z 596.29 [M+H]⁺.

[0945] 483 (100 mg) was resolved by prep-HPLC [Chiralpak AD-H (25 x 2 cm, 5 um), mobile phase: n-hexane/(ethanol+0.1% ipa) 80/20% v/v. flow rate: 14 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: a mixture of 498a and 498b: 32 mg (tR= 14.3 min); and a mixture of 498c and 498d: 31 mg (tR= 19.0 min).

[0946] The mixture of 498a and 498b (32 mg) was resolved by prep-HPLC [Chiralcel OJ-H (25 x 2 cm, 5 um), mobile phase: n-hexane/(ethanol/methanol +0.1% ipa) 55/45% v/v, flow rate: 17 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: 498a: 9.3 mg (tR= 5.7 min). UPLC/MS(ES⁺): m/z 596.25 [M+H]⁺; and 498b: 10.2 mg (t_R= 8.8 min). UPTC/MS(F.S⁺): m/z 596.25 [M+H]⁺.

[0947] The mixture of 498c and 498d (31 mg) was resolved by prep-HPLC [Chiralpak IC (25 x 2 cm, 5 um), mobile phase; n-hexane/(2-propanol +0.1% ipa) 55/45% v/v, flow rate: 18 mL/min, UV detection DAD 220 nm]. Two fractions were recovered based on retention times: 498c: 10 mg (t_R= 6.7 min). UPLC/MS(ES~): m/z 596.25 [M+H]⁺: and 498d: 8 mg (t|<= 10.5 min). UPLC/MS(ES⁺): m/z 596.25 [M+H]⁺.

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EXAMPLE 259

Preparation of Compound 499

/

Cl

[0948] A solution of 483 (30 mg) and chloroacetaldehyde (50% aq. solution, 30 uL) in MeOH (1.5 mL) was stirred at r.t. for 1 h. NaBH₃CN (2 mg) was added, and the mixture was stirred at r.t. for 18 h. The volatiles were removed under reduced pressure to afford a mixture of 499-1 and unreacted starting material (2:1), which was dissolved in DMF (1.5 mL). NaN₃ (10 mg) was added. The reaction -was stirred at 70 °C for 20 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 80:20 to 0:100) afforded 499-2 as a pale yellow oil (20 mg). UPLC/MS(ES⁺): m/z 665.30 [M+H]⁺.

[0949] A mixture of 499-2 (20 mg) and PPh₃ (10 mg) in 2:1 THF-PfO (1.5 mL) was stirred while heating to 60 °C for 2 h. The volatiles were removed under reduced pressure. The residue was loaded on to an SCX column and eluted with 2M NH₃-MeOH to afford 499 (7 mg). UPLC/MS(ES⁺): m/z 639.30 [M+H]⁺.

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EXAMPLE 260

Preparation of Compounds 530 and 531

[0950] Compounds 530 and 531 were prepared by using a strategy that follows the procedure described for 509.

[0951] l-Bromo-2-butanone (300 mg. 1.98 mmol) w^ras added to a solution of 5093 (1.00 g, 2.84 mmol) and potassium carbonate (520 mg. 4.26 mmol) in acetone (16.5 mL). The reaction was stirred at 50°C for 1 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated. The organic portion was dried with Na₂SO4, filtered and concentrated under reduced pressure. The residue was triturated with DCM-cyclohexane to afford 530-1 as a white solid (1.02 g, 85%). UPLC/MS(ES⁺): m/z 423.93 [M+H]⁺.

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PCT/US2014/051642 [0952] The reaction was performed in 2 batches. A mixture of 530-1 (510 mg, 1.20 mmol), 2-methylpropane-2-sulfinamide (160 mg, 1.32 mmol) and titanium(IV) ethoxide (602 mg, 2.64 mmol) in THF (9.5 mL) was heated to 70 °C (sealed vial, degassed and purged with 1%). The mixture was stirred at 70 °C for 4 h. The 2 batches were unified, and EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with +428()4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 95:5 to 60:40) afforded 530-2 (850 mg, 67%). UPLC/MS(ES⁺): m/z 527.00 [M+H]⁺.

[0953] EtMgBr (IM solution in THF, 1.61 mL, 1.61 mmol) was added to a solution of w-BuLi (1.6M solution in THF, 2.01 mL, 3.23 mmol) in dry THF (5 mL), which had been pre-cooled to 0°C. After 30 mins, the mixture w⁷as cooled to -78 °C. A solution of 530-2 (850 mg. 1.61 mmol) in dry THF (4 mL) w⁷as added dropw⁷ise, and the reaction was stirred at -78 °C for 20 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with water and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 30:70) afforded 530-3 as a white foam (441 mg).

[0954] Dess-Martin periodinane (932 mg, 2.20 mmol) was added to a stirred solution of 530-3 (441 mg) in DCM (5 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1:1 mixture of IM aq. Na₂S₂O3 and 5% aq. NaHCCq. After 20 min of vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na₂SO₄. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 0:100) afforded 530-4 as a white foam (320 mg, 50% over two steps). UPLC/MS(F.S⁺): m/z 417.10 [M+H₃O]⁺.

[0955] Trimethylsulfoxonium iodide (175 mg, 0.790 mmol) w'as added in one portion to a mixture of tBuOK (88 mg, 0.790 mmol) in CH3CN (15 mL). which had been previously degassed. The mixture w⁷as further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 530-4 (317

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PCT/US2014/051642 mg, 0.790 mmol) in CH₃CN (15 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 530-5 as a colorless wax (207 mg. 64%). UPLC./MS(ES⁺): m/z 413.12 [M+H]⁺.

[0956] A solution of 530-5 (207 mg) in 7M NH₃-MeOH (142 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford crude 530-6 (203 mg) which was directly progressed to the next step.

[0957] A mixture of acid (0.233 mmol), HATU (86 mg. 0.252 mmol) and DTPEA (58 uL. 0.336 mmol) in DCM (2 mL) was stirred at r.t. for 30 mins. A solution of 530-6 (100 mg) in DCM (2 mL) was added. The mixture was stirred at r.t. for 1 h. The reaction was partitioned between DCM and water, and the layers were separated. The organic portion was washed with brine, dried with Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by chromatography to give 530-7 or 530-8.

[0958] A mixture of 530-7 or 530-8 (0.134 mmol), 4-fluorophenylboronic acid (38 mg), K₃PO₄ (29 mg), KTEPCfi (18 mg) and Pd(dbpf)Cb (17 mg) in a DMEfotOLLHiO mixture (10:5:3, 3.6 mL) was degassed and warmed to 50 °C- 70 °C. DCM and water were added. The layers were separated. The organic portion was dried with NioSOj, filtered and concentrated under reduced pressure. The residue was purified by chromatography. A solution of sulfinamide (80 mg) in 4M HCl-dioxanc was stirred at r.t. for 10 mins. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography.

[0959] Coupling of 530-6 with 4-cyclopropoxy-3-methoxybenzoic acid afforded 530-7. which was subjected to Suzuki coupling and sulfinamide hydrolysis as described herein to afford 531 as a white solid (formic acid salt. 25% overall). UPLC/MS(ES⁺): m/z 576.30 [M+H]⁺.

[0960] Coupling of 530-6 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3methoxybenzoic acid afforded 530-8, which was subjected to Suzuki coupling and protecting groups removal as described herein to afford 530 as a white powder (26% overall). UPLC/MS(ES⁺): m/z 580.34 [M+H]⁺.

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EXAMPLE 261

Preparation of Compounds 560, 565 and 568

[0961] Compounds 560, 565 and 531 were prepared by using a strategy that follows the procedure described for 509.

[0962] 1 -Bromo-3-methylbutan-2-one (659 mg, 3.99 mmol) was added to a solution of 509-3 (2.01 g, 5.71 mmol) and potassium carbonate (1.18 g, 8.56 mmol) in acetone (34 mL). The reaction was stirred at 50°C for 1 h. The volatiles were removed under reduced pressure and the residue was partitioned between water and EtOAc. The layers w^rere separated. The organic portion was dried with Na^SOq, filtered and concentrated under reduced pressure. The residue w^ras tritured with cyclohexane and the precipitate dried to afford 560-1 as a white solid (1.38 g. 55%). UPLC/MS(ES⁺): m/z 438.10 [M+H]⁺.

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PCT/US2014/051642 [0963] A mixture of 560-1 (1.38 g, 3.15 mmol). 2-methylpropane-2-sulfinamide (419 mg, 3.46 mmol) and titanium(IV) ethoxide (1.58 g, 6.93 mmol) in T1 IF (25 mL) was heated to 70 °C (sealed vial, degassed and purged with N?) and stirred at 70 °C for 4 h. EtOAc and water were added. The mixture was filtered through a pad of celite. The layers were separated. The organic portion was dried with Na>SO₄ and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclo hexane :Et₂O. 90:10 to 60:40) afforded 560-2 (841 mg. 50%). UPLC/MS(ES⁺): m/z 541.10 [M+H]⁺.

[0964] w-Buthyllithium (1.6 M solution in THF. 1.93 mL, 3.10 mmol) was added to a solution of EtMgBr (IM solution in THF, 1.55 mL, 1.55 mmol) in THF (5 mF), which had been pre-cooled to 0°C. After 10 mins, the mixture w^ras cooled to -78°C. A solution of 560-2 (841 mg, 1.55 mmol) in THF (4 mL) was added drop wise and the reaction was stirred at -78 °C for 20 min. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with brine and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 30:70) afforded 5603 as a white foam (580 mg, 90%).

[0965] Dess-Martin periodinane (1.19 g, 2.80 mmol) was added to a sUrrcd solution of 560-3 (580 mg, 1.40 mmol) in DCM (10 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1:1 mixture of 2M aq. Na₂S₂O3 and sat. aq. NaUCCf. After 20 mins vigorous stirring, the layers were separated. The aqueous portion was extracted with DCM. The combined organic portions were dried with Na₂SCL. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 0:100) afforded 560-4 as a white foam (520 mg. 90%).

[0966] Trimethylsulfoxonium iodide (277 mg, 1.26 mmol) was added in one portion to a mixture of tBuOK (141 mg, 1.26 mmol) in CH3CN (20 mL). which had been previously degassed. The mixture was further degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution 560-4 (520 mg, 1.26 mmol) in CH3CN (20 mL). which had been previously degassed. The reaction was stirred at room temp for 15 min. Volatiles were removed under reduced pressure.

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Chromatography of the residue (cyclohexane:EtOAc. 80:20 to 50:50) afforded 560-5 as a colorless oil (311 mg, 58%). UPLC/MS(ES⁺): m/z 427.28 [M+I I] 7 [0967] A solution of 560-5 (311 mg, 0.730 mmol) in 7M NH₃-McOH (140 mL) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure to afford 560-6 (313 mg), which was directly progressed to the next step.

[0968] Method A: A mixture of 560-6 (155 mg. 0.350 mmol), acid (0.350 mmol), EDC (86.3 mg, 0.450 mmol). HOBT (61.4 mg, 0.450 mmol) and TEA (97 pL, 0.700 mmol) in DCM (5 mL) was stirred at r.t. for 2 h. Water was added and the mixture was stirred at r.t. for 10 mins. The layers were separated, and the organic portion was washed with brine, dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography⁷ of the residue (cyclohexane:EtOAc) afforded 560-7.

[0969] Method B: A mixture of acid (0.169 mmol), HATU (96.5 mg, 0.254 mmol), and DIPEA (59 uL, 0.338 mmol) in DMF (1 mL) was stirred at room temp for 30 min. A solution of aminol 560-6 (100 mg) in DML (1 mL) was added and the reaction was stirred at room temp for lh. EtOAc was added and the organic portion was washed twice with sat. aq. NH₄C1 solution, dried (Na2SO₄), filtered and concentrated under reduced pressure to afford 560-7, which w⁷as directly progressed to the next step.

[0970] A mixture of 560-7 (0.250 mmol), 4-fluorophenylboronic acid (104 mg, 0.740 mmol), K₃PO₄ (106 mg, 0.500 mmol), KH₂PO₄ (68 mg, 0.500 mmol) and Pd(dbpf)Cl₂(11 mg, 0.017 mmol) in a DME:EtOH:H₂O mixture (5:3:1, 18 mL) was degassed and warmed to 80 °C. After 3 h, EtOAc was added. The organic portion was washed with sat. aq. NH₄C1 solution, dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 560-8.

[0971] Method A: Hydrochloric acid (4M solution in dioxane, 2 mL) was added to a solution of 560-8 (152 mg) in MeOH (4 mL). After 10 mins, the volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 560-9.

[0972] Method B: A solution of 560-8 (0.089 mmol) in 4M HCl-dioxane (4 mL) w⁷as stirred at r.t. for 40 mins. The volatiles were removed under reduced pressure. The

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PCT/US2014/051642 residue was purified by reverse phase chromatography (water-CFfCN, 100:0 to 50:50) to afford 560-9.

[0973] Coupling of 560-7 with 4-cyclopropoxy-3-methoxybenzoic acid according to Method A afforded 560-8A (70%). UPLC/MS(ES⁺): m/z 634.33 [M+H]⁺.

[0974] Suzuki coupling of 560-8A with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis (Method A) afforded 560 as a white solid (43% over 2 steps). UPLC/MS(ES⁺): m/z 590.40 [M+H]⁺.

h₂n [0975]

Coupling of 560-7 with 4-(2-(4-methoxybenzyloxy)ethoxy)-3methoxvbenzoic acid according to Method B afforded 560-8B which was progressed to the next step without any purification.

[0976] Suzuki coupling of 560-8B with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis (Method B) afforded 565 as an off-white solid (13% overall). UPLC/MS(ES⁺): m/z 594.40 [M+H]⁺.

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h₂n [0977] Coupling of 560-7 with 4-[(2R)-2-hydroxypropoxy]-3-methoxybenzoic acid according to Method A afforded 560-8C (43%).

[0978] Suzuki coupling of 560-8C with 4-fluorophenylboronic acid followed by sulfinamide hydrolysis (Method A) afforded 568 (52% overall). UPLC/MS(ES⁺): m/z 608.50 [M+H]⁺.

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EXAMPLE 262

Preparation of Compounds 473, 474 and 475

[0979]

Formaldehyde (37% aq. solution, 30.4 mL, 407 mmol) was added in 4 portions to a mixture of 473-1 (15.0 g. 116 mmol) and NaHCO₃ (14.6 g. 174 mmol) in water (120 mL) which had been pre-heated to 90°C. The reaction was stirred at 90 °C for 16 h. Additional formaldehyde (37% aq. solution, 232 mmol) was added and the reaction was stirred at 90°C for 1 h. After being cooled to r.t., the reaction was concentrated under reduced pressure. The crude 473-2 was directly used in the next step.

[0980] Iodine (25 g. 98.4 mmol) was added to a mixture of 473-2 (13 g) and

KcCOs (22.0 g. 159 mmol) in water (100 mL). The mixture was stirred at r.t. for 4 h. The reaction was poured in to a IM aq. HC1 solution, which had been pre-cooled to 0 °C. The

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PCT/US2014/051642 aqueous portion was extracted with EtOAc (3x). The combined organic portions were dried with NajSO-i and filtered. The volatiles were removed under reduced pressure.

Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 0:100) afforded 473-3 as an off-white solid (5.4 g). 'H NMR (400 MHz. DMSO-J₆) δ ppm 4.41 (s, 2 H), 7.77 (s, 1 H),

10.37 (s. 1 H).

[0981] Chloroacetone (750 uL) was added to a mixture of 473-3 (2.41 g) and K2CO3 (1.69 g) in acetone (50 mL). The mixture was warmed to 50 °C and stirred at 50 °C for 16 h. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4 and filtered. The volatiles were removed under reduced pressure. Trituration of the residue with DCM:cyclohexane afforded 473-4 as a white solid (2.33 g). UPLC/MS(ES⁺): m/z 342.00 [M+H]⁺.

[0982] EtMgBr (IM solution in 2-methyltetrahydrofuran, 4.39 mL, 4.39 mmol) was added to a solution of w-BuLi (1.6 M solution in hexane. 5.48 mL. 8.78 mmol) in THF (10 mL). which had been pre-cooled to 0 °C. After 10 mins, the mixture was cooled to -78 °C. A solution of 473-4 (1.35 g, 3.96 mmol) in THF (8 mL) was added dropwise and the reaction was stirred at -78 °C for 2 h. The reaction was quenched with MeOH and diluted with EtOAc. The organic portion was washed with water, dried with NhtSO/ filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30 to 0:100) afforded 473-5 (619 mg, 72%). UPLC/MS(ES⁺): m/z 216.10 [M+H]⁺.

[0983] Alcohol 473-5 was split in 2 batches (2 x 305 mg) which were separately processed as described below. The 2 reactions were unified for work-up and purification procedures. A mixture of 473-5 (305 mg. 1.42 mmol), (3-chloro-4-fluorophenyl)boronic acid (617 mg, 3.54 mmol), Pd(dppf)C12 (104 mg, 0.142 mmol) and sodium carbonate (2M aq. solution, 2.49 mL, 5.00 mmol) in DCE (10 mL) was degassed and stirred with heating to 100°C under microwave irradiation for 1.5 h. DCM and water were added. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na2SC>4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50 to 0:100) afforded 473-6 (315

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PCT/US2014/051642 mg, 35%) and some unreacted 473-5 (94 mg). 473-6: ’Η NMR (400 MHz, CDC1₃) δ ppm

1.74 (s, 3 H), 4.48 (d,./-10.3 Hz, 1 H), 4.66 (d, ,/=10.3 Hz, 1 H), 4.75 (d, ,/=14.1 Hz, 1 H),

4.79 (d, /=14.1 IIz, 1 11), 7.22 (s, 1 II), 7.23 (t,/=8.7 Hz, 1 II), 8.18 (ddd,/=8.7, 4.7. 2.3 Hz,

H), 8.36 (dd,/=7.3, 2.3 Hz, 1 H).

[0984] Dess-Martin periodinane (365 mg. 0.861 mmol) was added to a stirred solution of 473-6 (315 mg, 1.02 mmol) in DCM (5 mL). The reaction was stirred at r.t. for 1.5 h. A 1:1 IM aq. Na?S2O₃:sat. aq. NaHCO₃ mixture was added to the reaction and the mixture was stirred at r.t. for 20 mins. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with Na₂SO4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane-EtOAc, 90:10 to 0:100) afforded 473-7 (266 mg, 85%). 'H NMR (400 MHz. CDCI3) δ ppm 1.57 (s, 3 H). 4.60 (d, /=10.3 Hz, 1 H). 4.82 (d. /=10.3 Hz. 1 H), 7.30 (t, /= 8.7 Hz, 1 H). 8.02 (s, 1 H), 8.32 (ddd. /=8.7, 4.6, 2.3 Hz, 1 H), 8.50 (dd, /=7.3, 2.3 Hz. 1 H). 10.11 (s, 1 H).

[0985] Trimethylsulfoxonium iodide (191 mg, 0.866 mmol) was added to a solution of tBuOK (97 mg, 0.866 mmol) in DMSO (3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 473-7 (266 mg. 0.866 mmol) in DMSO (3 mL) was added and the mixture was stirred at r.t. for 30 mins. The reaction was diluted with EtOAc and water. The layers were separated and the aqueous portion was extracted with EtOAc. The combined organic portions were washed with brine, dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20 to 0:100) afforded 473-8 (81 mg, 29%). ‘H NMR (400 MHz. CDCI3) δ ppm 1.75 (2 x s. 3 H), 3.003.04 (m, 1 H), 3.24 (dd, /=5.1, 4.4 Hz, 1 H), 4.11- 4.15 (m, 1 H) 4.48 (d. /=10.0 Hz, 1 H), 4.68 (d./=10.0 Hz, 1 H). 7.20 - 7.28 (m. 2 H), 8.21 - 8.28 (m. 1 H). 8.40 - 8.46 (m. 1 H).

[0986] Λ solution of 473-8 (81 mg. 0.252 mmol) in 7M NH₃-MeOH (50 mL) was stirred at r.t. for 20 h. The volatiles were removed under reduced pressure. Crude 473-9 was directly used in to the next step.

[0987] A mixture of 4-cyclopropoxy-3-methoxybenzoic acid (63 mg. 0.302 mmol), HATU (144 mg. 0.378 mmol) and DIPEA (88 uL, 0.504 mmol) in DMF (1 mL) was stirred at r.t. for 30 mins. A solution of 473-9 in DMF (2 mL) was added and the mixture

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PCT/US2014/051642 was stirred at r.t. for 1 h. EtOAc was added The organic portion was washed with brine, dried with Na?SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH, 100:0 to 80:20) afforded 473-10 (82 mg). UPLC/MS(ES⁺): m/z

529.30 [M+H]⁺.

[0988] Dess-Martin periodinane (65 mg, 1.57 mmol) was added to a solution of 473-10 (80 mg, 0.151 mmol) in DCM (5 mL). The reaction was stirred at r.t. for 10 mins. A 1:1 IM aq. Na?S2O₃:sat. aq. NaHCCE, mixture was added. The mixture was stirred at r.t. for 20 mins. The layers were separated and the aqueous portion was extracted with DCM. The combined organic portions were dried with boo SO i and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30 to 0:100) afforded 473 (24 mg, 18% over 3 steps) and 474 (19 mg, 15% over 3 steps). 473: white solid; UPLC/MS(ES⁺): m/z 527.30 [M+H]⁺. 474: off-white solid; UPLC/MS(ES⁺): m/z 509.30 [M+H]⁺.

[0989] MeMgBr (3M solution in EtjO, 30 uL, 0.090 mmol) was added to a solution of 473 (16 mg, 0.030 mmol) in THF (2.5 mL). The reaction was stirred at r.t. under N₃ atmosphere for 30 mins. EtOAc and water were added. The layers were separated and the aqueous portion extracted with EtOAc. The combined organic portions were dried with Na₃SO4 and filtered. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 30:70 to 0:100) afforded 475 as a white solid (6 mg, 37%). UPLC/MS(ES⁺): m/z 543.30 [M+HJ⁺.

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EXAMPLE 263

Preparation of Compounds 479 and 480

[0990] A mixture of 479-1 (1.00 g. 7.75 mmol), (4-fluorophenyl) boronic acid (2.17 g, 15.5 mmol), Pd(dppf)C12 (566 mg, 0.775 mmol) and sodium carbonate (2M aq solution, 7.75 mL, 15.5 mmol) in DCE (70 mL) was degassed and stirred with heating to 85 °C overnight. Water and DCM were added. The layers were separated and the organic phase was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforded 479-2 as a white solid (990 mg, 67%). 'H NMR (400 MHz. DMSO-7₆) δ ppm 7.16 - 7.29 (m, 3 H), 7.34 (dd, 7=8.2, 1.4 Hz, 1 H), 8.04 8.12(m,2H), 8.15 (dd, 7=4.4, 1.4 Hz, 1 H), 10.22 (s, 1 H).

[0991] Potassium carbonate (1.15 g, 8.34 mmol) and trifluoroacetaldehyde ethyl hemiacetal (740 uL, 6.26 mmol) were added to a suspension of 479-2 (790 mg, 4.17 mmol) in water (15 mL). The mixture was stirred at 100 °C overnight. Additional trifluoroacetaldehyde ethyl hemiacetal (327 uL, 2.70 mmol) was added and the reaction was stirred at 100 °C overnight. The reaction was cooled to 0°, neutralized with IM aq HCI solution and extracted with EtOAc. The organic portion was dried with Na₂SO4. filtered and

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PCT/US2014/051642 concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc,

100:0 to 50:50) afforded 479-3 as a white solid (1.08 g, 90%). ’ll NMR (400 MIIz, DMSOJ₆) δ ppm 5.00 - 5.14 (m, 1 II), 6.83 (d,./-6.3 IIz, 1 II). 7.23 - 7.30 (m, 2 II). 7.42 (s, 2 II),

8.07 - 8.15 (m, 2 H), 10.48 (s, 1 H).

[0992] NaH (195 mg. 4.87 mmol) was added to a stirred solution of 479-3 (1.08 g, 3.75 mmol) in DMF (11 mL). which had been pre-cooled to 0° C. The mixture was stirred at 0° C for 10 mins, then warmed to r.t. and stirred for 30 mins. The reaction was cooled to 0° C and chloroacetonitrile (260 uL, 4.13 mmol) was added dropwise. The mixture was allowed to gradually reach r.t. and stirring was continued for 20 h. EtOAc and sat. aq. NH4CI were added. The layers were separated. The organic portion was washed with brine, dried with Na2SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-4 as a colorless wax (1.10 g. 90%). 'H NMR (400 MHz, DMSO-J₆) δ ppm 5.12 - 5.25 (m, 1 H). 5.33 (s, 2 H). 7.02 (d. ./=6.0 Hz, 1 H), 7.30 - 7.37 (m, 2 H), 7.67 (d, ./=8.7 Hz, 1 H), 7.83 (d, ,7=8.7 Hz, 1 H), 7.91 7.98 (m. 2 H).

10993] L1AIH4 (IM solution in THF. 3.17 mL, 3.17 mmol) was added dropwise to a stirred solution of 479-4 (940 mg, 2.80 mmol) in THF (20 mL) which had been pre-cooled to 0°C. The mixture was warmed to r.t. and stirred for 30 mins. The reaction was cooled to 0 °C. Water (3 mL) was slowly added, followed by IN aq. NaOH solution (3 111L) and more water (9 mL). EtOAc was then added, and the layers were separated. The organic portion was washed with brine, dried with Na2SO4. filtered and concentrated under reduced pressure. The crude 479-5 was directly used in the next step.

[0994] Di-tert-butyl dicarbonate (610 mg, 2.80 mmol) and DMAP (34.0 mg, 0.280 mmol) were added to a solution of 479-5 in DCM (10 mL). After 2 h, water was added and the layers were separated. The organic portion was dried with Na2SO4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 50:50) afforted a di-protected compound. This di-protected compound was dissolved in CH3CN (2 mL). A IM aq. NaOH solution (2 mL) was added and the reaction was stirred at 50 °C for 1 h. Most of the solvents were removed under reduced pressure and the pH of the resulting solution was adjusted to 7 with IM aq. HC1. The aqueous portion was extracted

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PCT/US2014/051642 with EtOAc. The organic layer was dried with Na₂SO4, filtered and evaporated under reduced pressure. Chromatography of the residue (cyclohcxanciEtOAc, 100:0 to 50:50) afforted 479-6 as a white solid (235 mg). UPLC/MS(ES⁺): m/z 431.38 [M+H]⁺.

[0995] Dess-Martin periodinane (274 mg. 0.640 mmol) was added to a stirred solution of 479-6 (235 mg. 0.540 mmol) in DCM (9 mL). The reaction was stirred at r.t. under N₂ atmosphere overnight and quenched with a 1:1 2M aq. Na₂S₂O3:sat. aq. NaHCO₃mixture. After 30 mins, the layers were separated. The organic portion was washed with brine, dried with Na₂SC>4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 479-7 as a white solid (144 mg. 62%). UPLC/MS(ES⁺): m/z 447.29 [M+H₃0]⁺.

[0996] Trimethylsulfoxonium iodide (57.0 mg, 0.260 mmol) was added to a solution of tBuOK (29.0 mg, 0.260 mmol) in DMSO (3 mL). The mixture was stirred at r.t. for 30 mins. A solution of 479-7 (112 mg. 0.260 mmol) in THF (3 mL) was added, and the mixture was stirred at r.t. for 30 mins. The mixture was diluted with EtOAc and water, and the layers were separated. The aqueous layer was extracted w^rith EtOAc. The combined organic portions were washed with brine, dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane.EtOAc, 100:0 to 50:50) afforded 479-8 (44 mg) and unreacted 479-7 (53 mg). 479-8: UPLC/MS(ES⁺): m/z 443.29 [M+H]'.

[0997] A solution of 479-8 (44 mg) in 7M NH₃-McOH (2 mL) was stirred with heating to 45° C for 40 mins. The volatiles were removed under reduced pressure. Crude 479-9 (45 mg) was directly used in the next step.

[0998] A mixture of 479-9 (45 mg). EDC (23 mg. 0.12 mmol). HOBT (17 mg. 0.12 mmol), TEA (33 uL, 0.24 mmol) and 4-cyclopropoxy-3-methoxybenzoic acid (20 mg. 0.098 mmol) in DCM (1 mL) was stirred at r.t. for 2 h. Water w'as added, and the mixture was stirred for 10 mins. The layers were separated. The organic portion was dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography (cyclohexane:EtOAc. 100:0 to 40:60) afforded 479-10 as a white solid (53 mg). LJPLC/MS(ES⁺): m/z 650.40 [M+H]⁺.

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PCT/US2014/051642 [0999] TFA (350 uL) was added to a solution of 479-10 (53 mg, 0.081 mmol) in DCM (2 mL). The mixture was stirred at r.t. for 30 mins. Water was added, and the layers were separated. The organic portion was dried with Na₂SO4, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water: CH_SCN, 100:0 to 40:60) to afford 479 (A/l 587/35/1) as a white solid (30 mg, 67%). UPLC/MS(ES⁺): m/z 550.32 [M+H]⁺.

[1000] Formaldehyde (37% aq. solution, 3 uL) was added to a solution of 479 (17 mg, 0.030 mmol) in MeOH (200 uL). The mixture was stirred at r.t. for 3 h. Sodium cyanoborohydride (1.8 mg, 0.030 mmol) w’as added, and the reaction was stirred at r.t. for 10 mins. The solvents were removed under reduced pressure. Water and DCM were added. The layers were separated. The organic portion was dried with Na₂SO4. filtered and concentrated under reduced pressure. Chromatography of the residue (DCM:MeOH, 100:0 to 90:10) afforded 480 as a white solid (2 mg, 10%). UPLC/MS(ES⁺): m/z 578.40 [M+H]⁺.

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EXAMPLE 264

Preparation of Compounds 506 and 507

OMe OMe

[1001] LDA (2M solution, 39.4 mL. 78.7 mmol) was added to a solution of 507-1 (5.00 g, 39.4 mmol) in dry THF (100 mL). which had been pre-cooled to -78° C. The mixture was stirred at -78 °C for 1 h. Dimethylcarbonate (8.0 mL, 95.0 mmol) was added, and the temperature was raised to 0 °C. Lhe reaction was stirred at 0 °C for 30 mins and then partitioned between EtOAc and sat. aq. NH4CI solution. The organic phase was purified by

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66%).

[1002] Tctrakis(triphenylphosphine)-palladium(0) (1.18 g, 1.03 mmol) was added to a mixture of 507-2 (3.8 g, 20.5 mmol), (4-fluorophenyl)boronic acid (4.30 g. 30.8 mmol) and Na?CO3 (5.4 g, 51.3 mmol) in 1:1 dioxane-FEO (60 mL). which had been previously degassed by bubbling N2. Lhe reaction was stirred at 120 °C for 2 h. UPLC analysis of the reaction showed that Suzuki coupling was followed by hydrolysis of the methyl ester. The mixture was concentrated under reduced pressure. The residue was dissolved in MeOH and cone. H2SO4 was added. The reaction was warmed to 50 °C and stirred at 50 °C for 2 h. EtOAc was added. The mixture was cooled to 0 °C and quenched with a sat. aq. K2CO3 (final pH 8). The layers were separated, and the organic portion was concentrated under reduced pressure. Chromatography of the residue (DCM:cyclohexane, 50:50) afforded 507-3 (2.66 g, 53%). UPLC/MS(ES⁺): m/z 246.20 [M+H]⁺.

[1003] LHMDS (IM solution in THF, 11.9 mL, 11.9 mmol) was added dropwise to a solution of 507-3 (2.66 g, 10.8 mmol) in THF (40 mL), which had been pre-cooled to -78 °C. The mixture was stirred at -78 °C for 1 h. Methyl iodide (740 pL, 11.9 mmol) was added and the reaction w^ras allowed to gradually reach r.t. After being stirred at r.t. for 16 h, the reaction was cooled to 0 °C and quenched with sat. aq. NaHCO₃ solution. The aqueous portion was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 80:20) afforded 507-4 (1.70 g, 61%). UPLC/MS(ES⁺): m/z 260.10 [M+HJ⁺.

[1004] LHMDS (IM solution in THF, 7.22 mL. 7.22 mmol) was added dropwise to a solution of 507-4 (1.70 g, 6.56 mmol) in THF (12 mL). which had been pre-cooled to -78 °C. The mixture was stirred at -78 °C for 1 h. A solution of bromoacetonitrile (503 uL. 7.22 mmol) in THF (12 mL) was added, and the reaction was allowed to gradually reach r.t. After being stirred at r.t. for 2 h, the reaction was cooled to 0 °C and quenched with sat. aq. NH4CI solution. The aqueous portion was extracted with EtOAc. The organic layer was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 50:50) afforded 507-5 (1.91 g, 98%). 'H NMR (400 MHz, DMSOA) d ppm 1.76 (s. 3 H).

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3.37 (d, ,/=17.0 Hz, 1 H), 3.44 (d, ./=17.0 Hz, 1 H), 3.72 (s, 3 H), 7.31 - 7.40 (m, 3 H), 7.90 (d, 7=1.5 Hz, 1 H), 8.15 - 8.23 (m, 2 H), 8.68 (d, 7=5.3 Hz, 1 H).

[1005] Nickel Raney (0.600 mmol) was added to a solution of 507-5 (1.91 g, 6.40 mmol) in MeOH (50 mL). The reaction was stirred at 60 °C under H2 atmosphere (5 bar) for 3 h. The reaction was filtered through a pad of celite and the solution was refluxed for 4 h. DIPEA (1 eq.) was added, and the mixture was refluxed for 30 mins. The volatiles were removed under reduced pressure. The residue was dissolved in EtOAc. The organic portion was washed with sat. aq. NaHCO3 solution, dried and concentrated under reduced pressure. Chromatography of the residue (EtOAc:MeOH. 100:0 to 95:5) afforded 507-6 (870 mg. 50%). UPLC/MS(ES⁺): m/z 271.20 [M+H]⁺.

[1006] L1AIH4 (2M solution in THF, 3.03 mL, 6.06 mmol) w⁷as added to a solution of 507-6 (820 mg, 3.03 mmol) in THF (18 mL), which had been pre-cooled to 0 °C. The reaction was stirred at r.t. for 1 h. then warmed to 70 °C and stirred at 70 °C for 30 mins. The reaction w⁷as cooled to 0 °C and Na₂SC>4*10 H?O and Et₂O w⁷ere added. The mixture was filtered through a pad of celite, and the solution concentrated under reduced pressure. Crude 507-7 (720 mg) was directly used in the next step.

[1007] A mixture of 507-7 (720 mg) and sat. aq. NaHCOs solution (16 111L) in dioxane (9 mL) was cooled to 0 °C. A solution of FmocCl (764 mg, 2.95 mmol) in dioxane (9 mL) was added, and the reaction was allowed to reach r.t. After 1 h, the reaction was diluted with EtOAc. The organic portion was washed with water and brine, dried and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 50:50) afforded 507-8 (1.10 g. 49% over 2 steps). UPLC/MS(ES⁺): m/z 479.40 [M+H]⁺.

[1008] /«-Chloroperbenzoic acid (797 mg. 4.62 mmol) was added to a solution of 507-8 (1 .10 g, 2.31 mmol) in DCM (30 mL). The reaction was stirred at r.t. overnight. EtOAc w⁷as added. The organic phase w⁷as washed with sat. aq. K2CO3 sol and concentrated under reduced pressure. Crude 507-9 (1.17 g) was directly used in the next step.

[1009] A mixture of 507-9 (1.17 g) and POCI3 (50 mL) was stirred at 60 °C for 12 h. The volatiles were removed under reduced pressure. EtOAc and water were added, and the mixture was basified by adding sat. aq. KHCO3 solution (final pH 8). The layers were separated, and the organic portion w^ras concentrated under reduced pressure.

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Chromatography of the residue (cyclohexane:EtOAc, 90:10 to 0:100, then EtOAc:MeOH,

80:20) afforded 507-10 (700 mg, 58%) and unreacted starting material 507-9 (300 mg). 50710: UPLC/MS(ES⁺): m/z 513.27 [M+H]⁺.

[1010] Tributyl[1-ethoxyethenyI]stannane (552 uL. 1.63 mmol) and Pd(PPh0Cl?

(199 mg, 0.284 mmol) were sequentially added to a solution of 507-10 (700 mg, 1.36 mmol) in dioxane (4 mL), which had been previously degassed by bubbling N₂. The mixture was further degassed and stirred at 100 °C for 1 h. After being cooled to r.t.. the mixture was partitioned between EtOAc and sat. aq. KF solution. The layers were separated. The organic portion was washed with IM aq. HCI solution, dried and concentrated under reduced pressure. Chromatography of the residue (cyclohexane.’EtOAc. 80:20) afforded 507-11 (670 mg, 95%). UPLC/MS(ES⁺): m/z 521.32 [M+H]⁺.

[1011] Hydrobromic acid (33% solution in AcOH, 377 uL, 2.08 mmol) and bromine (53 uL, 1.04 mmol) were added to a solution of 507-11 (541 mg. 1.04 mmol) in dioxane (10 mL). which had been pre-cooled to 0 °C. The reaction was stirred at r.t. for 2 h. Additional bromine (0.5 eq.. 27 pL) was added and stirring was prolonged for 2 h. The reaction was quenched with water and neutralized with sat. aq. Nall CO; solution. The aqueous portion was extracted with DCM. The organic layer was dried with Na₂SC>4 and concentrated under reduced pressure. Chromatography of the residue (DCM:EtOAc, 60:40) afforded 507-12.

[1012] TMSCF3 (430 mg, 3.00 mmol) and CsF (91 mg) were sequentially added to a solution of 507-12 (90 mg) in THF (12 mL). The reaction was stirred at r.t. for 20 mins. The mixture was partitioned between EtOAc and IM aq. HCI solution. The layers were separated, and the organic portion was concentrated under reduced pressure. Crude 507-13 was directly used in the next step.

[1013] A solution of 507-13 in ammonia (7M solution in MeOH, 5 mL) was stirred at r.t. for 1.5 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc-MeOH, 60:30:10) afforded 507-14 (44 mg). UPLC/MS(ES⁺): m/z 606.40 [M+H]⁺.

[1014] A solution of 4-cyclopropoxy-3-methoxybenzoic acid (20.0 mg. 0.095 mmol), DIPEA (50 uL, 0.270 mmol) and HATU (39.0 mg. 0.102 mmol) in DCM (4 mL) was

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PCT/US2014/051642 stirred at r.t. for 30 mins. A solution of 507-14 (41.0 mg, 0.068 mmol) in DCM (1 mL) was added. The reaction was stirred for 16 h, quenched with MeOII (10 mL) and stirred for 1 h.

The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 100:0 to 60:40) afforded 507-15 as a colorless oil (23 mg. 42%).

UPLC/MS(ES⁺): m/z 796.50 [M+H]⁺.

[1015] Morpholine (1 mL) was added to a solution of 507-15 (23 mg. 0.029 mmol) in DMF (1 mL), and the solution was stirred for 1 h. The volatiles were removed under reduced pressure. Chromatography of the residue (NH-cartridge. cyclohexane:EtOAc:MeOH, 100:0:0 to 60:30:10) afforded 507 (10 mg. 60%).

UPLC/MS(ES⁺): m/z 574.30 [M+H]⁺.

[1016] Formaldehyde (37% aq. solution. 30 uL, 0.350 mmol) and NaBH(OAc)3 (22.0 mg, 0.105 mmol) were added to a solution of 507 (4.0 mg, 0.007mmol) in DCM (2 mL). Lhe reaction was vigorously stirred overnight, quenched with IM aq. NaOH solution and extracted with DCM. The volatiles were removed under reduced pressure. The residue was purified by SCX-chromatography to afford 506 as a colorless oil (2.4 mg, 58%). UPLC/MS(ES⁺): m/z 588.50 [M+H]⁺.

EXAMPLE 265

Preparation of Compounds 519, 520,521,527 and 523

OMe

General Suzuki coupling conditions [1017] Method A: A mixture of 519-1 (70 mg. 0.112 mmol), boronate/boronic acid (0.170 mmol), KH2PO4 (15.3 mg, 0.112 mmol), K3PO4 (24.0 mg, 0.112 mmol) and

Pd(dbpf)C12 (7.5 mg, 0.011 mmol) in DME:H₂O:EtOH (1:0.5:0.3, 1.8 mL) was degassed and

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PCT/US2014/051642 heated to 50 °C for 24 h. The mixture was partitioned between Et₃O and water. The organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 519-2.

[1018] Method B: A mixture of 519-1 (90 mg. 0.145 mmol), boronic acid (0.322 mmol), Pd2(dba)₃ (15 mg. 0.016 mmol), PCy₃ (10 mg, 0.038 mmol) and K3PO4 (85 mg. 0.402 mmol) in dioxane (1 mL)- water (300 uL) was degassed and heated to 100 °C for 12 h. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 519-2.

Protecting group(s)-removal:

[1019] Method A: Aqueous HCI (6M solution, 4 mL) was added to a solution of 519-2 (0.056 mmol) in isopropanol (2.5 mL). The reaction was heated to 95 °C for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography to afford 519-3.

[1020] Method B: A mixture of 519-2 (0.047 mmol) and Pd/C (9 mg) in MeOH (4.7 111L) was stirred under IL atmosphere for 5 h. The mixture was filtered from the catalyst, and the solution was treated with IM HCI solution in EbO. The volatiles were removed under reduced pressure. The residue was triturated with EuO to afford 519-3 as its hydrochloride salt.

[1021] Method C: TMSC1 (32 uL) and Nal (39 mg) were sequentially added to a solution of 519-2 (0.089 mmol) in CH₃CN (4 mL). The reaction was stirred at r.t. for 1 h, warmed to 45 °C and stirred at that temp for 16 h. Additional TMSC1 (64 uL) and Nal (80 mg) were added, and the reaction was stirred at 45 °C for 5 h. The volatiles were removed under reduced pressure. The residue was partitioned between EtOAc and a 1:1 mixture of 5% aq. NaHCO₃:lM aq. Na2S2O₃. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4, fdtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography to give 519-3.

[1022] Method D: Hydrobromic acid (33% solution in AcOH, 30 uL) was added to a solution of 519-2 (20 mg) in 4M HCl-dioxane (2 mL). The reaction was warmed to 70 °C. When complete Cbz-removal w⁷as observed by UPLC, the reaction w⁷as concentrated

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PCT/US2014/051642 under reduced pressure. The residue purified by reverse phase chromatography to afford 5193.

[1023] Method E: A mixture of 519-2 (9.1 mg) in 4M HCT-dioxanc (2 mL) was warmed to 70 °C (or 100 °C). When complete Cbz-removal was observed by UPLC. the reaction was concentrated under reduced pressure, and the residue purified by reverse phase chromatography to afford 519-3.

[1024] Suzuki coupling of 519-1 with 1 -((2-(trimethylsilyl)ethoxy)methyl)-7fluoro-3-(4.4,5.5-tetramethyl-L3.2-dioxaborolan-2-yl)-lH-indole (Method A) followed by protecting groups removal according to Method A afforded 519 as its hydrochloride salt (white solid, 16% overall). UPLC/MS(ES⁺): m/z 587.36 [M+H]⁺.

[1025] Suzuki coupling of 519-1 with 4-chlorophenylboronic acid (Method A) followed by Cbz-rcmoval according to Method A afforded 520 as its hydrochloride salt (white solid, 24% overall). UPLC/MS(ES⁺): m/z 564.30 [M+H]⁺.

[1026] Suzuki coupling of 519-1 with 4-fluoro-3-(trifluoromethyl)phenylboronic acid (Method A) followed by Cbz-removal according to Method B afforded 521 as its hydrochloride salt (45% overall). UPLC/MS(ES⁺): m/z 616.38 [M+H]⁺.

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[1027] Suzuki coupling of 519-1 with 4-cvanophenylboronic acid (Method A) followed by Cbz-removal according to Method C afforded 527 as its formic acid salt (white solid, 37% overall). UPLC/MS(ES⁺): m/z 555.40 [M+H]⁺.

OMe

[1028] Suzuki coupling of 519-1 with 4-(triiluoromethyl)phenylboronic acid (Method A) followed by Cbz-removal according to Method B afforded 523 (5% overall). UPLC/MS(ES⁺): m/z 598.30 [M+EI]⁺.

EXAMPLE 266

Preparation of Compound 524

[1029] Suzuki coupling of 519-1 (310 mg) with 2-(4-fluoro-3-nitrophenyl)-5,5dimethyl-l,3,2-dioxaborinane (Method A of Example 265) afforded 519-2A (35 mg). UPLC/MS(ES⁺): m/z 727.30 [M+H]⁺.

[1030] Iron powder (8 mg, 0.144 mmol) was added to a solution of 519-2A (35 mg, 0.05 mmol) in 2:2:1 EtOHiAcOH-ELO (2.5 mL). The mixture was heated to 80 °C for 1

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h. The reaction was filtered through a pad of celite, and the volatiles were evaporated under reduced pressure. The crude was partitioned between EtOAc and aq. NaHCOj solution, and the organic portion was purified by chromatography to afford 519-4 (30 mg).

UPLC/MS(ES⁺): m/z 697.40 [M+H]⁺.

[1031] Aniline 519-4 (30 mg) was dissolved in CH3CN (2 mL) under N₂atmosphere. f-BuONO (14 mg. 0.129 mmol) was added. The mixture was stirred at r.t. for 30 mins. CuBr (6.2 mg. 0.043 mmol) was added, and the mixture was stirred for 2.5 h. The reaction w^ras partitioned between DCM and sat. aq. NH4CI solution. The organic phase w^ras purified by chromatography to recover 519-5 (12 mg).

[1032] Deprotection of 519-5 according to Method A of Example 265 afforded 524 as its hydrochloride salt (1.2 mg). UPLC/MS(ES⁺): m/z 626.30 [M+H]⁺.

EXAMPLE 267

Preparation of Compounds 557 and 567

[1033] Suzuki coupling of 519-1 with 2-chloropyridine-5-boronic acid (Method B of Example 265) followed by treatment of the resulting Cbz-protected amine witli TMSCl/Nal according to Method C of Example 265 afforded 557 (5% overall). UPLC/MS(ES+): m/z found 657.32 [M+H]⁺.

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PCT/US2014/051642 [1034] Deprotection of 519-2B according to Method E of Example 265 afforded

567 (16%). UPLC/MS(ES⁺): m/z 565.40 [M+H]⁺.

EXAMPLE 268

Preparation of Compound 558

OMe Cl

[1035] Suzuki coupling of 519-1 with 2-chloropyridine-4-boronic acid (Method B of Example 265) followed by Cbz-removal according to Method D of Example 265 afforded

558 (3% overall). UPLC/MS(ES⁺): m/z 565.30 [M+H]⁺.

EXAMPLE 269

Preparation of Compound 559

[1036] Suzuki coupling of 519-1 with 3-cyano-4-fluorophenylboronic acid (Method A of Example 265) followed by Cbz-removal according to Method D of Example 265 afforded 559 (10% overall). UPLC/MS(ES⁺): m/z 573.42 [M+H]⁺.

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EXAMPLE 270

Preparation of Compound 514

OEt

[1037] NaBLL (808 mg, 21.3 mmol) was added to a solution of 514-1 (3.10 g, 17.7 mmol) in MeOH (22 mL), which had been pre-cooled to 0 °C. The mixture was allowed to reach r.t. and stirring was prolonged for 30 mins. 1M aq. HC1 solution was added, and the organic solvent was removed under reduced pressure. The aqueous phase was extracted with DCM (3x). The combined organic portions were dried with Na^SCff and filtered. The volatiles were removed under reduced pressure to afford 514-2 (3.01 g). UPLC/MS(ES⁺): m/z 178.00 [M+H]⁺.

[1038] Chloromethyl methyl ether (704 pL. 9.27 mmol) and TEA (1.75 mL, 12.6 mmol) were added to a solution of 514-2 (1.5 g) in DCM (12 mL). The reaction was warmed to 45 °C. When complete conversion was observed by UPLC, the reaction was cooled to r.t.. diluted with DCM and washed with water. The organic portion was concentrated under

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PCT/US2014/051642 reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30) afforded 5143 (1.48 g). UPLC/MS(ES⁺): m/z 222.00 [M+H]⁺.

[1039] A mixture of 514-3 (1.38 g, 6.24 mmol), Pd(PPh₃)Cl₂ (438 mg, 0.624 mmol) and tributyl[l-ethoxyethenyl]stannane (2.11 mL, 6.24 mmol) in dioxane (40 mL) was degassed, warmed to 90 °C and stirred at that temp for 3 h. After being cooled to r.t., the reaction was diluted with EtOAc. The organic portion was washed with a sat. aq. KF solution and water, dried with Na₂SO4, filtered and concentrated under reduced pressure to afford crude 514-4, which w’as directly used in the next step.

[1040] NBS (888 mg, 4.99 mmol) was added to a solution of 514-4 in THF (40 mL), which had been pre-cooled to 0 °C. The reaction w^?as stirred at 0 °C for 1 h. then warmed to r.t., and stirred for 2 h. EtOAc w'as added. The organic portion was washed with water, dried with Na₂SO4. filtered and concentrated under reduced pressure. Chromatography of the residue (cvclohexaneiEtOAc, 100:0 to 70:30) afforded 514-5 (1.11 [1041] CF₃TMS (6 mL) w⁷as added to a solution of 514-5 (1.11 g) in THF (15 mL). CsF (2.74 g, 18.0 mmol) was added in 1 portion. After 1 h, the reaction was partitioned between EtOAc and sat. aq. NH4CI solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO4, filtered and concentrated under reduced pressure. Crude 514-6 was directly used in the next step.

[1042] A solution of 514-6 and 7M NH₃-MeOH (50 mL) was stirred at r.t. for 16 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN. 100: 0 to 50:50) to afford 514-7 (214 mg). UPLC/MS(ES⁺): m/z 315.30 [M+H]⁺.

[1043] A mixture of 514-7 (291 mg, 0.928 mmol), EDC (212 mg. 1.11 mmol). HOBT (150 mg, 1.11 mmol), TEA (310 uL, 2.23 mmol) and 4-cyclopropoxy-3methoxybenzoic acid (193 mg, 0.924 mmol) in DCM (6 mL) was stirred at r.t. for 2 h. A IM aq. HC1 solution was added, and the mixture was stirred for 2 mins. The layers were separated. The organic portion was washed with IM aq. NaOH solution, and concentrated

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PCT/US2014/051642 under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 70:30) afforded 514-8 (140 mg, 30%). UPLC/MS(ES⁺): m/z 505.20 [M+I I]^H.

[1044] A mixture of 514-8 (67.6 mg, 0.134 mmol), 4-fluorophcnylboronic acid (28 mg. 0.201 mmol), KH?PO₄ (21 mg. 0.134 mmol), K₃PO₄ (29.0 mg. 0.134 mmol) and Pd(dbpf)Cl? (9 mg, 0.013 mmol) in DME-HiO-EtOH (5:3:1. 5 mL) was degassed and heated to 50 °C for 48 h. The mixture was partitioned between DCM and water. The organic portion was concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 70:30) afforded 514-9 (50.7 mg). 'H NMR (400 MHz. CDC1₃) δ ppm 0.80-0.90 (m. 4 H). 3.36 (s. 3 H). 3.72 - 3.81 (m. 1 H). 3.85 (s, 3 H). 3.97 (dd. 7=14.0. 3.5 Hz, 1 H). 4.58 (s, 2 H), 4.62-4.73 (m. 3 H), 6.43 (dd. 7=7.9. 3.5 Hz. 1 H). 6.67 (s, 1 H). 7.08 (dd. ./=8.3. 1.8 Hz. 1 H), 7.14 - 7.22 (m, 3 H). 7.25 (d. .7=1.8 Hz, 1 H), 7.53 - 7.61 (m. 2 H). 7.78 (d, ./=8.1 Hz, 1 H), 8.05 (d, ./=8.1 Hz, 1 H).

[1045] A solution of 514-9 (50.7 mg, 0.09 mmol) in 1:1 DCM-TFA (700 pL) was stirred at r.t. for 12 h. The reaction was diluted with DCM. The organic portion was washed with 2M aq. NaOH solution and concentrated under reduced pressure. Crude 514-10 (45 mg) was directly used in the next step. UPLC/MS(ES⁺): m/z 521.30 [M+H]⁺.

[1046] TEA (19 pL, 0.136 mmol) and MsCl (10 pL, 0.133 mL) were sequentially added to a solution of 514-10 (45 mg) in DCM (1 mL), which had been pre-cooled to 0 °C. The reaction was allowed to reach r.t.. stirred for 12 h and diluted with DCM. The organic portion was washed with water, dried with Na₂SO₄, filtered and concentrated under reduced pressure. Crude 514-11 (36 mg) was directly used in the next step.

[1047] A solution of 514-11 (36 mg) in 7M NH₃-MeOH (1 mL) was stirred at r.t. for 12 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (water:CH₃CN, 100:0 to 67:33) to afford 514 (19.6 mg). UPLC/MS(ES⁺): m/z 520.30 [M+H]⁺.

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EXAMPLE 271

Preparation of Compound 538

nh₂ [1048] A 0.2 M solution of 538-1 (465 mg, 1.14 mmol) in toluene (5.7 mL) was degassed (mw vial). Pd(Q-phos)2 (80 mg, 0.052 mmol) was added. The vial was sealed, purged with N2 and heated to 100 °C for 6 h. Additional Pd(Q-phos)2 (30 mg) was added. The vial was purged with N2 and heated to 100 °C for 4 h. The mixture was directly purified by chromatography on silica gel (cyclohexane:EtOAc, 95:5 to 70:30) to afford 538-2 (414 mg, 96%). UPLC/MS(ES⁺): m/z 408.10 [M+H]⁺.

[1049] A mixture of 538-2 (340 mg) and NaNj (288 mg) in DMF (4 mL) was heated to 65 °C and stirred at that temp for 16 h. The volatiles were removed under reduced pressure. The crude residue was partitioned between EtOAc and sat. aq. NH4CI solution. The layers were separate. The organic portion was dried with Na2SO4. filtered and concentrated under reduced pressure to afford 538-3 (245 mg). UPLC/MS(ES⁺): m/z 323.10 [M+H]⁺.

[1050] Dess-Martin periodinane (484 mg, 1.14 mmol) was added to a solution of 538-3 (245 mg) in DCM (4 mL). The reaction was stirred at r.t. for 1 h and quenched with a 1:1 IM aq. Na?S2O3:5% aq. NaHCOs. The mixture was vigorously stirred for 1 h. The layers were separated, and the aqueous portion was extracted with DCM. The combined

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PCT/US2014/051642 organic portions were dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc) afforded 538-4 (206 mg). UPLC'/MS(ES⁺): m/z 339.10 [M+H₃0]⁺.

[1051] Trimethylsulfoxonium iodide (141 mg. 0.643 mmol) was added in one portion to a mixture of tBuOK (72 mg, 0.643 mg) in CH₃CN (4 mL), which had been previously degassed. After 20 mins, the solution was filtered from the solid and added to a solution of 538-4 (206 mg) in CH₃CN (4 mL), which had been previously degassed. The reaction was stirred at r.t. for 15 mins. The volatiles were removed under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 538-5. UPLC/MS(ES⁺): m/z 335.10 [M+H]⁺.

[1052] A solution of 538-5 (100 mg) in 7M NH₃-MeOH (60 mL) was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure to afford crude 538-6 (108 mg), which was directly used in the next step. UPLC7MS(ES⁺): m/z 352.10 [M+H]⁺.

[1053] A mixture of 538-6 (108 mg), EDC (89 mg, 0.462 mmol). HOBT (63 mg, 0.462 mmol), 4-cyclopropoxy-3-methoxybenzoic acid (64 mg, 0.307 mmol) and TEA (86 uL, 0.616 mmol) in DCM (4 mL) was stirred at r.t. for 16 h. The reaction w^ras diluted with DCM. The organic portion was washed with IM aq. HC1 solution (2x), dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 100:0 to 50:50) afforded 538-7 (136 mg). UPLC/MS(ES⁺): m/z 542.20 [M+H]⁺.

[1054] Pd(dbpf)CI₂ (16 mg. 0.025 mmol) was added to a mixture of 538-7 (136 mg), K₃PO₄ (107 mg, 0.503 mmol). I<H₂PO₄ (68 mg. 0.503 mg) and 4-fluorophenylboronic acid (74 mg, 0.503 mmol) in 5:3:1 DME:EtOH:H₂O (2.7 mL). which had been previously degassed. The reaction was warmed to 65 °C and stirred at that temp for 10 h. The mixture was cooled to r.t. and stirred for 72 h. The reaction was diluted with EtOAc and washed with sat. aq. NH₄CI solution. The organic portion was dried with Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (wateLO. |% HCOOH:CH₃CN/O.l% HCOOH, 100:0 to 50:50) to afford 538 as a white solid (formic acid salt, 33 mg. dr 1:1). UPLC/MS(ES⁺): m/z 576.40 [M+H]⁺.

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EXAMPLE 272

Preparation of Compound 522

OMe OMe

[1055] tfze/tf-Chloroperbenzoic acid (56.0 g. 328 mmol) was added in several portions to a solution of 2-chloro-4-methylpyridine (20.0 g. 156 mmol) in DCM (520 mL). The mixture was refluxed for 8 h and diluted with DCM. The organic portion was washed with sat. aq. K2CO3 solution. The aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na2SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (DCMiMeOH, 100:0 to 80:20) afforded 522-1 as a yellow oil (9.50 g. 42%). UPLC/MS(ES⁺): m/z 144.00 [M+H]⁺.

[1056] POCI3 (130 mL) was added to a solution of 522-1 (9.50 g. 66.0 mmol) in toluene (20 mL). The reaction was heated to 70 °C and stirred at that temp for 20 h. The volatiles were removed under reduced pressure. The residue was poured into ice. The mixture neutralized with sat. aq. K2CO3 solution and extracted with DCM (3x). The combined organic portions were dried with Na2SO₄. filtered and concentrated under reduced

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PCT/US2014/051642 pressure. Chromatography of the residue afforded 522-2 (3.80 g, 36%). UPLC/MS(ES⁺):

m/z 162.10 [M+I I]^H.

[1057] A freshly prepared solution of LDA solution (IM in THF-hexane, 44.6 mL. 44.6 mmol) was added to a solution of 522-2 (3.61 g. 22.3 mmol) in THF (110 mL). which had been pre-cooled to -78 °C. The reaction was stirred at -78 °C for 1 h. Dimethylcarbonate (4.5 mL, 53.5 mmol) was added. The reaction was allowed to reach 0 °C. stirred at that temp for 1 h and quenched with water. The volatiles removed under reduced pressure. The residue was taken up with EtOAc. The organic portion was washed with sat. aq. NH4CI solution, dried with Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane :EtO Ac, 100:0 to 60:40) afforded 522-3 as a yellow oil (3.0 g, 61%). UPLC/MS(ES⁺): m/z 220.0 [M+H]⁺.

[1058] A mixture of 522-3 (450 mg, 2.00 mmol), 3-chloro-4-fluorophenylboronic acid (285 mg, 1.60 mmol), NaHCCfl (515 mg. 6.10 mmol) and Pd(PPh₂)4 (95 mg, 0.080 mmol) in 2:1 THF:water (9 mL) was degassed and heated to 50 °C. After 2 h, 3-chloro-4tluorophenyl boronic acid (0.2 eq.) was added, and the mixture was stirred at 50 °C for 2 h. After being cooled to r.t., the reaction was diluted with DCM. The organic portion was washed with sat. aq. Nal IC( L solution, dried with Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by reverse phase chromatography (water:CI I3CN, 70:30 to 10:90) to afford 522-4 as a yellow oil (180 mg, 29%). UPLC/MS(ES⁺): m/z 314.10 [M+H]⁺.

[1059] 522-4 (860 mg, 2.70 mmol) was dissolved in 7M NH₃-MeOH (14 mL) at 0 °C. The reaction was stirred at r.t. for 3 h and at 40 °C for 20 h. The volatiles were removed under reduced pressure to afford crude 522-5 (775 mg), which was directly used in the next step.

[1060] Borane-THF complex (IM solution in THF, 7.77 mL. 7.77 mmol) was added to a solution of 522-5 (775 mg) in THF (14 mL). The reaction was refluxed for 3 h. Additional borane-THF complex (4 eq., 2 aliquots) was added, and the mixture was refluxed overnight. The reaction was quenched with 2M aq. HCI solution, and the mixture was stirred for 30 mins . The aqueous portion was basified with sat. aq. NaHCO?, solution and extracted with EtOAc. The organic portion was washed with brine, dried with Na₂SO4, filtered and

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PCT/US2014/051642 concentrated under reduced pressure. The residue was loaded on to a SCX-column and eluted with 2M NIL-MeOlI to give 522-6 (610 mg, 82%). UPLC/MS(ES^H): m/z 285.10 [M+H]⁺.

[1061] Triethylamine (590 uL, 4.26 mmol) and BOC2O (700 mg, 3.20 mmol) were sequentially added to a solution of 522-6 (610 mg. 2.13 mmol) in DCM (11 mL). The reaction was stirred at r.t. for 1 h, diluted with DCM and washed with 0.5M aq. HC1 solution. The organic portion was dried with Na₂SO4. filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 90:10 to 50:50) afforded 5227 as a white solid (580 mg, 71 %). UPLC/MS(ES⁺): m/z 385.20 [M+H]⁺.

[1062] A mixture of 522-7 (580 mg. 1.50 mmol). Pd(PPh3)Cl₂ (105 mg. 0.150 mmol) and tributyl[1-ethoxyethenyl]stannane (560 uL. 1.65 mmol) in dioxane (8 mL) was degassed, warmed to 100 °C and stirred at that temp for 6 h. After being cooled to r.t., a sat. aq. KF solution was added. The mixture was stirred for 10 mins, and the aqueous portion was extracted with EtOAc. The organic phase was dried with Na₂SO₄. filtered and concentrated under reduced pressure to afford crude 522-8, which was directly used in the next step.

[1063] .V-Bromosuccinimide (293 mg, 1.65 mmol) was added to a solution of 522-8 in THF (8 mL), which had been pre-cooled to 0 °C. The reaction was stirred at 0 °C for 1 h, quenched with water and extracted with EtOAc. The organic portion was dried with Na₂SO₄, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc, 90:10 to 50:50) afforded 522-9 as a white solid (330 mg. 47% over 2 steps). 'H NMR (400 MHz, CDC1₃) δ ppm 1.45 (s, 9 H), 3.00 (t, ./-6.5 Hz, 2 H), 3.50 (q, J=6.5 Hz, 2 H). 4.58 - 4.69 (m. 1 H). 4.95 (s, 2 H). 7.30 (t. 7=8.0 Hz. 1 H). 7.79 (br. s.. 1 H). 7.92 (s. 1 H), 7.95 - 8.02 (m, 1 H), 8.15 (dd, 7=6.9, 2.1 Hz, 1 H).

[1064] CF3TMS (1.03 mL, 7.00 mmol) was added to a solution of 522-9 (330 mg. 0.700 mmol) in THF (5 mL). CsF (531 mg, 3.50 mmol) was added in one portion. After 1 h. the reaction was partitioned between EtOAc and sat. aq. NH₄CI solution. The layers were separated, and the aqueous portion was extracted with EtOAc. The combined organic portions were dried with Na₂SO₄, filtered and concentrated under reduced pressure. The crude 522-10 was directly used in the next step.

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PCT/US2014/051642 [1065] A solution of 522-10 and 7M NHj-MeOH (10 mL) was stirred at r.t. for 3 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (wateriCLLCN, 95:5 to 30:70) to afford 522-11 (56 mg).

[1066] A mixture of 4-cyclopropoxy-3-methoxybenzoic acid (49.0 mg. 0.230 mmol), HATU (108 mg. 0.280 mmol) and DIPEA (122 uL, 0.700 mmol) in DCM (1 mL) was stirred at r.t. for 30 mins. A solution of 522-11 (56 mg) in DCM (1 mL) was added, and the reaction was stirred at r.t. for 2 h and quenched with water. EtOAc was added. The organic portion was washed with IM aq. HC1 solution, 2M aq. NaOH solution and brine, dried with Na2SO4, filtered and concentrated under reduced pressure. Chromatography of the residue (cyclohexane:EtOAc. 90:10 to 40:60) afforded 522-12 (65 mg).

[1067] A solution of 522-12 in 4M HCl-dioxane (1 mL) was stirred at 0 °C for 1 h. The volatiles were removed under reduced pressure. The residue was purified by reverse phase chromatography (wateriCLfCN, 95:5 to 40:60) to afford 522 (14 mg). UPLC/MS(ES⁺): m/z 568.30 [M+H]⁺.

EXAMPLE 273

Preparation of Compound 477

[1068] A mixture of 271-10 (50 mg, 0.1 mmol), 477-1 (16 mg, 0.1 mmol) and TEA (1 mmol) was dissolved in anhydrous DCM (4 mL) with stirring. The mixture was treated with HATU (38 mg. 0.1 mmol) in 1 portion. After stirring at r.t. for 30 mins, TFA (1 mL) was added. The solution was stirred at r.t. for 2 h. The mixture was concentrated to dryness. The residue was purified by reverse prep-HPLC to afford 477 (28 mg, 48%) as a white solid. +ESI-MS: m/z 537.1 [M+H]⁺.

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EXAMPLE 274

Preparation of Compound 478

[1069] Compound 478 was prepared following the general procedure for preparing 477 by using 2-chloiOoxazole-4-carboxylic acid and 271-10. Crude 478 was purified by prep-HPLC and obtained as a white solid (20 mg, 36%). +ESI-MS: m/z 520.9 [M+H]⁺.

EXAMPLE 275

Preparation of Compound 485

485-1 485-2 485-3 485-4

485-6 271-10

[1070] To a solution of 485-1 (6 g, 15.4 mmol) in anhydrous DMF (95 mL) was added NaH (640 mg, 16 mmol. 60% in mineral oil) in small portions at r.t. After stirring for 10 mins, a solution of Mel (2.3 g, 16 mmol) in DMF (5 mL) was added dropwise, and the reaction was stirred for 1 h. After complete conversion of 485-1, the mixture was quenched with water, and extracted with EtOAc (150 mL x 2). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by chromatography using (PErEtOAc: 100:0 to 80:20) to afford 485-2 (5.8 g, 93.5%).

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PCT/US2014/051642 [1071] Compound 485 (white solid, 27 mg) was prepared following the general procedure for preparing 272 using 485-2 and (S)-3-methoxy-4-((2-oxopyrrolidin-3yl)oxy)benzoic acid. +ESI-MS: m/z 639.1 [M+H]⁺.

EXAMPLE 276

Preparation of Compound 486

[1072] Compound 486 (white solid, 34 mg) was prepared following the general procedure for preparing 485 by using 486-1 and 271-10. +ESI-MS: m/z 614.1 [M+H]⁺.

EXAMPLE 277

[1073] Compound 487 (white solid, 27.5 mg) was prepared following the general procedure for preparing 485 by using 487-1 and 271-10. +ESI-MS: m/z 613.1 [M+H]^T.

EXAMPLE 278

Preparation of Compound 488 q/

271-10

[1074] Compound 488 (white solid, 26 mg) was prepared following the general procedure for preparing 485 by using 488-1 and 271-10. +F.SI-MS: m/z 591.1 [M+H]⁺.

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EXAMPLE 279

Preparation of Compound 489

[1075] Compound 489 (white solid. 23 mg) was prepared following the general procedure for preparing 485 by using 489-1 and 271-10. +ESI-MS: m/z 586.0 [M+H]⁺.

EXAMPLE 280

Preparation of Compound 490

[1076] Compound 490 (white solid, 41 mg) was prepared following the general procedure for preparing 485 by using 490-1 and 271-10. +ESI-MS: m/z 656.0 [M+H]⁺.

EXAMPLE 281

Preparation of Compound 491

[1077] Compound 491 (white solid. 25 mg, 44 %) was prepared following the general procedure for preparing 485 by using 491-1 and 491-2. +ES1-MS: m/z 600.1 [M+H]⁺.

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EXAMPLE 282

Preparation of Compounds 495 and 496

o' o'

[1078] To a solution of 495-1 (850 mg, 1.73 mmol) in MeOH (50 mL) was added Pd/C (210 mg, 5%) under N₂ at r.t. The suspension was purged with hydrogen for several times. The mixture was stirred under hydrogen (15 psi) at r.t. for 12 h. After complete conversion of 495-1, the mixture was filtered through a pad of Celite, and the filtrate was concentrated to dryness. The residue was 495-2 (750 mg, 94.6%), which was used directly without further purification. +ESI-MS: m/z 458.2 [M+H]⁺.

[1079] A mixture of 495-2 (750 mg, 1.64 mmol), carboxyl acid 3 (340 mg, 1.64 mmol) and TEA (1 mmol) is dissolved in anhydrous DMF (10 mL) with stirring. The solution was treated with HATU (623 mg, 1.64 mmol) in one portion. After stirring at r.t. for 1~2 h, the mixture was poured into cold water and extracted with ΕΛ (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4, and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 495-3 as an oil (910 mg, 86%). +EST-MS: m/z 648.1 [M+H]⁺.

[1080] To a stirring solution of 495-3 (910 mg. 1.41 mmol) in DCM (10 ml,) was added TFA (5 mL) dropwise at r.t. The reaction was stirred for 30 mins and concentrated to dryness under reduced pressure. The residue was neutralized by sat. sodium carbonate solution and extracted with EA (15 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue

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PCT/US2014/051642 was purified by prep-HPLC and separated by SFC, to give 495 (93 nig) and 496 (82 mg) as a white solid.

495: +ESI-MS: m/z 548.1 [M+H]⁺; and 496: +ESI-MS: m/z 548.1 [M+H]⁺.

EXAMPLE 283

Preparation of Compound 497

[1081] To a stirring solution of 314 (116 mg, 0.2 mmol), 2-((tertbutoxvcarbonyl)amino)acetic acid (35 mg, 0.20 mmol) and DIPEA (90 mg, 0.7 mmol) in anhydrous DCM (5 mL) was added HATU (76 mg, 0.2 mmol) in one portion at 25 °C. The solution was stirred for 1 h. The mixture was diluted with water and DCM. The organic layers were washed with brine, dried over anhydrous bwoSO i and concentrated under reduced pressure to give crude 497-1 (110 mg), which used directly without purification. +ESI-MS: m/z 739.1 [M+H]⁺.

|1082] To a stirring solution of crude 497-1 (110 mg) in EA (TO mL) was added HC1:EA (4 M, 5 mL) at r.t. The reaction was stirred for 30 mins with TLC monitoring. After conversion of 497-1, the reaction w^ras quenched with sat. sodium bicarbonate solution, and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NajSCfi and concentrated to dryness. The residue was purified by prepHPLC to give 497 (50 mg, 52.6%) as a white solid. +ES1-MS: m/z 639.2 [M+H]⁺.

EXAMPLE 284

Preparation of Compound 500

[1083] To a solution of 314 (58 mg. 0.1 mmol) and K2CO3 (27 mg, 0.2 mmol) in

DMF (1 mL) was added methyl 2-bromoacetate (23 mg. 0.15 mmol) at r.t. The mixture was

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PCT/US2014/051642 heated to 60 °C and stirred for 2 h. The reaction was cooled to r.t. and diluted with H₂O and

EA. The combined organic layer was dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 500 as a white solid (30 mg,

16.'%). +ESI-MS: m/z 654.1 [M+H]⁺.

EXAMPLE 285

Preparation of Compound 501

[1084] To a solution of 500 (90 mg. 0.14 mmol) in MeOH (10 mL) was added NH.yMeOH (7M, 10 mL). The vial was sealed and heated to 60 °C for 2 h. The reaction was cooled to r.t. and diluted with H₂O (20 mL) and EA (20 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated to dryness. The residue was purified by prep-HPLC to give 501 as a white solid (49 mg, ’ ·). +ES1-MS: m/z 639.1 [M+H]⁺.

EXAMPLE 286

Preparation of Compound 502

[1085] To a solution of 500 (65 mg, 0.1 mmol) in co-solvent of THF (2 mL) and MeOH (2 mL) was added L1BH4 (10 mg. 0.5 mmol) at r.t. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with H₂O and extracted with EA (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated to dryness at low⁷ pressure. The residue was purified by prep-HPLC to give 502 as a white solid (40 mg, 64.5%). +ESI-MS: m/z 626.0 [M+H]⁺.

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EXAMPLE 287

Preparation of Compound 503

[1086] To a solution of 503-1 (1.0 g, 2.5 mmol) in toluene (8 mL) was added pyridine (590 mg. 7.5 mmol) at 0 °C. The mixture was stirred at 0 °C for 5 mins and SOCL (820 mg, 7.0 mmol) was added dropwise. After addition, the mixture was stirred at 0 °C for 30 mins. The reaction was quenched with TEO and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous N;bS()| and concentrated to dryness. The residue was purified by column chromatography using PE:EA=5:1 as the eluent to give 503-2 as a solid (0.8 g, 85.1%). +ES1-MS: m/z 377.1 [M+H]⁺.

[1087] To a solution of 503-2 (0.8 g, 2.1 mmol) in DMSO (6 mf) was added ammonia water (1 mL) at 0 °C. The mixture was stirred at r.t. for 30 mins. The mixture was diluted with I CO and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaiSCL and concentrated to dryness. The residue was purified by column chromatography using PE:EA= + - as the eluent to give 503-3 as a solid . ^_ ). +ESI-MS: m/z 394.1 [M+H]⁺.

[1088] To a solution of 503-3 (n50 mg, 1.7 mmol) in MeOH (10 mL) was added Raney Ni (0.7 g) under N₂. The suspension was degassed under vacuum and purged with H₂for several times. The reaction was stirred under H₂ (balloon) at r.t. for 30 mins. The mixture was filtered through a pad of Celite, and the filtrate was concentrated to give 503-4 (.550 mg), which was used directly without purification.

[1089] To a solution of 503-4 (37 mg, 0.10 mmol). 4-cyclopropoxy-3methoxybenzoic acid (21 mg. 0.10 mmol) and DIPEA (39 mg, 0.3 mmol) in anhydrous DCM (3 mL) was added HATU (39 mg, 0.10 mmol) in one portion at 25 °C. The solution was

WO 2015/026792

PCT/US2014/051642 stirred at this temperature for 1 h. The reaction was diluted with H₂O and extracted with

DCM (10 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na₂SO i and concentrated to dryness at low pressure. The residue was purified by prep-HPLC to give 503 as a white solid (35 mg, 63.6%). +ES1-MS: m/z 553.9 [M+H]⁺.

EXAMPLE 288

Preparation of Compound 504

o

[1090] Compound 504 (white solid, 49 mg) was prepared following the general procedure for preparing 503 by using 503-1. +ESI-MS: m/z 581.2 [M+H]⁺.

EXAMPLE 289

Preparation of Compound 505 o'”

H [1091] Compound 505 (white solid, 9 mg) was prepared following the general procedure for preparing 500 by using 314 and 1 -bromo-2-methoxyethane as starting material. +ES1-MS: m/z 640.1 [M+H]⁺.

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EXAMPLE 290

Preparation of Compound 508

[1092] To a solution of 314 (290 mg, 0.5 mmol) in THF (5 mL) was added 2chloroacetaldehyde (0.5 g, 40 % in H₂O) at r.t. The mixture was stirred for 30 mins and NaBIl .CNi (160 mg. 2.5 mmol) was added. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with H₂O and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SC>4 and concentrated to dryness. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 508-1 as a solid (210 mg, 65.4%).

[1093] To a solution of 508-1 (2 H; wg. 0.33 mmol) in DMSO (5 mL) was added NaN₃ (6f- mg, 0.92 mmol) at r.t. The mixture was stirred at 60 °C for 30 mins. The mixture was cooled to r.t. and diluted with H₂O and EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated to give crude 508-2 (199 mg) as a pale yellow solid, which was used directly without purification. +ESI-MS: m/z 651.1 [M+H]⁺.

[1094] To a solution of 508-2 ( - . 0.29 mmol) in MeOH (15 mL) was added

Pd/C (0.2 g) under N₂ at r.t. The suspension was degassed under vacuum and purged with H? for several times. The mixture was stirred under H₂ balloon for 30 mins at r.t. The mixture was filtered through a pad of Celite. and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC to give 508 as a white solid (101 mg. 55.5%). +ESIMS: m/z 625.0 [M+H]⁺.

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EXAMPLE 291

Preparation of Compound 515

[1095] To a solution of 500 (180 mg, 0.28 mmol) in MeOH (5 mL) was added a solution of NaOH (50 mg. 1.25 mmol) in I LO (5 mL) at r.t. Elie mixture was stirred at 60 °C for 1 h. MeOH was evaporated, and the aqueous phase was acidified to pH = 1 by addition of 1 N HC1 solution. The solution was extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous NaiSOi and concentrated at low pressure. The residue was purified by prep-HPLC to give 515 as a white solid (80 mg, 45.0%). +ES1-MS: m/z 640.0 [M+H]⁺.

EXAMPLE 292

Preparation of Compound 516

[1096] To a solution of 314 (100 mg, 0.17 mmol) in DCM (2 mL) was added CCI3CONCO (36 mg, 0.189 mmol) at 0 °C. The solution was stirred for 20 mins. The solution was diluted with DCM (10 mL) and H2O (10 mL). Lhe organic phase was separated and concentrated under reduced pressure to give crude 516-1 (78 mg. 60.0%). which was used directly without purification.

[1097] To a solution of 516-1 (78 mg, crude) in MeOH (1 mL) was added sat. NaHCOi solution (1 mL) and stirred at r.t. for 1 h. The mixture was extracted with EA (lOmL x 3). The combined organic layers were washed by brine, dried over anhydrous Na₂SO4 and concentrated at low pressure. The residue was purified by prep-HPLC to give 516 (28 mg, 44.4%) as a white solid. +ESI-MS: m/z 625.1 [M+H]⁺.

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EXAMPLE 293

Preparation of Compound 517 o o

[1098] Compound 517 (white solid, 87 mg, 35.3%) was prepared following the general procedure for preparing 232 and 504 by using 517-1 and ethyl 2,2-difluoroacetate. +ES1-MS: m/z 536.0 [M+H]⁺.

EXAMPLE 294

Preparation of Compound 518

[1099] To a solution of 518-1 (3.56 g, 10.0 mmol) and CsF (3.0 g. 20.0 mmol) in MeCN (15 mL) was added 18-crown-6 (3.6 g. 13.6 mmol) at r.t. The mixture was heated to

100 °C and stirred at 100 °C for 5 h. The mixture was cooled to r.t., and the solid was removed by filtration. The filtrate was concentrated and purified by column chromatography

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PCT/US2014/051642 using PE:EA=5:1 as the eluent to give 518-2 as a solid (2.01 g, 67.3%). +ESI-MS: m/z 297.9 [M+II]⁺.

[1100] Compound 518 (white solid, 21 mg, 45.3%) was prepared following the general procedure for preparing 503 by using 518-2. +ESI-MS: m/z 518.0 [M+H]⁺.

EXAMPLE 295

Preparation of Compound 525

[1101] To a solution of 525-1 (2.8 g, 10.0 mmol) and AIBN (168 mg. 1.0 mmol) in CCI4 (20 mL) was added NBS (1.9 g. 10.7 mmol) at r.t. The mixture was heated to 70 °C and stirred for 3 h. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by column chromatography using PE;EA=15:1 as the eluent to give 525-2 as a solid (2.5 g, 69.8%). +ES1-MS: m/z 359.9 [M+H]⁺.

[1102] To a solution of 525-2 (2.5 g. 7.0 mmol) in DMSO (15 mL) was added NaN.3 (1.1 g, 16.9 mmol) at r.t. Lhe reaction was heated to 60 °C and stirred for 1 h. Lhe reaction was cooled to r.t. Lhe mixture was diluted with 1 E( ) and extracted with EA (60 111L x 3). The organic layers were dried over anhydrous Na₂S( )|. and concentrated under reduced

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PCT/US2014/051642 pressure. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 525-3 as a solid (1.8 g, 81.8%). +ESI-MS: m/z 322.8 [M+I I]¹.

[1103] To a solution of 525-3 (1.8 g, 5.6 mmol) in MeOH (15 mL) was added SnCL ^FEO (2.5 g, 11.1 mmol) at r.t. The mixture was stirred for 1 h with TLC monitoring. After 525-3 was consumed, the reaction was quenched with sat. NaHCOa and extracted with EA (30 mL x 2). The combined organic solution was dried over anhydrous Na^SCfi. and concentrated under reduced pressure. Crude 525-4 (1.0 g) was used directly without further purification.

[1104] To a solution of 525-4 (1.0 g, 3.4 mmol) in DCM (15 mL) was added BocaO (1.4 g, 6.4 mmol) at r.t. The mixture was stirred at r.t. for 3 h and then concentrated to dryness. The residue was purified by chromatography using PE:EA=5:1 as the eluent to give 525-5 as a solid (0.8 g, 61.5%).

[1105] To a solution of 525-5 (0.8 g, 2.0 mmol) and CFsCOOEt (1.7 g. 11.9 mmol) in THE (10 mL) was added isopropylmagnesium chloride (4 mL, 2.0 M in THF) dropwise at r.t. under Ni. The mixture was stirred at r.t. for 30 mins. The reaction was quenched with aq. NH4CI and extracted with EA (20 mL x 3). The combined organic solution was dried over anhydrous NaiSCfi, and concentrated under reduced pressure. Crude 525-6 (0.6 g) was used directly without purification.

[1106] Compound 525 (white solid, 130 mg) was prepared following the general procedure for preparing 272 using 525-6. +ESI-MS: m/z 582.1 [M+I I]⁺.

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EXAMPLE 296

Preparation of Compound 526

|U07] To a solution of 526-1 (10 g. 0.05 mol) in anhydrous DCM (100 mL) was added oxalyl dichloride (12.7 g. 0.1 mmol) and several drops of DMF. The mixture was stirred for 1 h and evaporated under reduced pressure to give 526-2.

[1108] To a solution of 2-methylbut-3-yn-2-amine (4.4 g. 52.5 mmol) and ELN (10.1 g, 0.1 mmol) in anhydrous DCM (100 mL) was added a solution of crude 526-2 in DCM (50 mL) dropwise at r.t. The solution was stirred for 1 h, washed with water and brine (50 mL). dried with anhydrous NasSO-i and concentrated to give 526-3. The residue was used directly without further purification.

[1109] 526-3 (2.58 g. 10 mmol) in PhNO₂ (10 mL) was put in a microwave tube.

The solution was heated to 210 °C by microwave irradiation and stirred for 5 mins. The reaction was cooled to r.t. and concentrated at low pressure. The residue was purified by column chromatography using PI^;.:FA 10:11:1 to give 526-4 (610 mg, 31.1%). +ESLMS: m/z 197.1 [M+H]⁺.

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PCT/US2014/051642 [1U0] To a stirring solution of DMAE (1.068 g, 12 mmol) in THF (10 mL) was added n-BuLi (10 mL, 25 mmol) at -78 °C. After 5 mins, a solution of 526-4 (588 mg, 3 mmol) in anhydrous THF (3 mL) was added dropwise at -78 °C. The mixture was stirred for 10 mins and a solution oft? (6.35g, 25 mmol) in THF was added dropwise at -78 °C. After 20 mins, the reaction was quenched with sat. aq. NaiSCf. The solution was extracted with EA (50 mL x 2). The organic phase was washed with brine and dried over anhydrous N028()4. The organic phase was concentrated at low pressure, and the residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 526-5 (650 mg, 51.0%).

SI-MS: m/z 322.9 [M+H]⁺.

[1111] To a solution of 526-5 (642 mg, 2 mmol) and CFiCOOEt (468 mg, 4 mmol) in anhydrous THF (5 mL) was added iPrMgCl (3 mL, 6 mmol) dropwise at r.t. The solution was stirred for 10 mins. The reaction was quenched with water and extracted with EA (20 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na?SO4, and concentrated to dryness. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 526-6 (302 mg, 51.3%).

[1112] To a solution of 526-6 (300 mg, 1.03 mmol) in DME/HiO (4 mL/Ι mL), CS2CO3 (502 mg, 1.55 mmol), (3-chloro-4-fluorophenyl)boronic acid (270 mg, 1.87 mmol) and Pd(dppf)C12 (50 mg, 65 mmol) were added at r.t. under N?. The vial was sealed and heated to 100 °C for 40 mins by microwave irradiation. After cooling to r.t., the mixture was diluted with EA (10 mL) and brine (10 mL). The aqueous layer was extracted with EA (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SC>4. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to give 526-7 (310 mg. 73.7%). +ESI-MS: m/z 386.9 [M+H]⁺.

[1113] To a solution of 526-7 (310 mg. 0.76 mmol) in div THF (5 ml.) was added BHrMeiS (1 mL. 10 mmol) at r.t. The solution was stirred in a pre-heated 80 °C oil bath for 2 h. The solution was cooled to r.t., and the reaction was quenched with H2O. The mixture was extracted with EA (20 mL x 2). The combined organic phase was washed with brine, dried over anhydrous JASCfi and concentrated under reduced pressure. The residue was

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PCT/US2014/051642 purified by column chromatography using EA as the eluent to give 526-8 (140 mg, 49.2%) as a gray solid.

[1114] To a solution of 526-8 (140 mg, 0.37 mmol) in toluene (3 mL) was added Et₃N (75 mg. 0.74 mmol) and BOC2O (87 mg, 0.44 mmol) at r.t. The solution was stirred in a pre-heated 100 °C oil bath for 3 h. The solution was cooled to r.t. and diluted with EA (20 mL) and water (20 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=5:1 as the eluent to give 526-9 (90 mg, 51.0%). +ESI-MS: m/z 474.9 [M+H]⁺.

[1115] To a stirred solution of 526-9 (90 mg, 0.189 mmol) in DMSO (2 mL) was added IBX (212 mg, 0.75 mmol) in one portion, and stirred at 40 °C for 2 h. The solution was poured into aq. Nal 1CC); and extracted with EA (10 mL x 2). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue w^ras purified by column chromatography using 0-30% EA in PE as the eluent to give 526-10 (60 mg, 66.7%).

[1116] Compound 526 (white solid, 4 mg, 13.7%) was prepared following the general procedure for preparing 272 using 526-10. +ES1-MS: m/z 594.1 [M+H]⁺.

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EXAMPLE 297

Preparation of Compound 528

528-6 528-7 528-8 528-9

[1117] To a stirred solution of 528-1 (50 g. 310 mmol) in anhydrous THF (1.2 L) was added LDA (310 mL. 620 mmol) at -78 °C slowly under N₂. and the mixture stirred at 78 °C for 0.5 h. A solution of dimethyl carbonate (67.1 g, 750 mmol) in dry THF (150 mL) was added dropwise. The solution was allowed to warm to 0 °C and stirred for 1 h below 0 ^l’C. The reaction was quenched with aq. NH4CI (500 mL), and extracted with EA (500 mL x 3). The combined organic phase was washed with aqueous sodium bicarbonate, brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to dry ness, and the residue was purified by column chromatography (PE:EA = 20:1) to give 528-2 (50 g, 73.5 %) as a colorless oil.

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PCT/US2014/051642 [1118] To a solution of crude 528-2 (50 g, 230 mmol) in dioxane:H₂O (6:1) (1 L) was added (3-chloro-4-fluorophenyl) boronic acid (40 g, 230 mmol), Cs₂CO₃ (223.3 g, 680 mmol) and Pd(dppf)CI? (16.8 g, 23 mmol) under N₂. The mixture was degassed for 3 times and refilled with N₂. The reaction was stirred at 80 °C in a pre-heated oil bath for 4 h. After cooling to r.t.. the mixture was diluted with water (1.5 L) and extracted with EA (1 L x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=20:l~15:l) to yield 528-3 (42 g. 58.7%) as a light yellow solid.

[1119] To a solution of 528-3 (9.39 g, 30.00 mmol) in HOAc (100 mL) was added Br₂ (5.28 g, 33 mmol) dropwise at r.t. The mixture was heated at 60 °C for 5 h. The reaction was cooled to r.t. and concentrated under reduced pressure to dryness. The residue was used directly without further purification. +ES1-MS: m/z 393.7 [M+H]⁺.

[1120] To a solution of crude 528-4 (10.0 g) in MeOH (100 mL) was added NaN₃(3.3 g, 50.8 mmol) at 25 °C, and the mixture was stirred at 25°C for 1 h. The mixture was diluted willi H₂O (150 mL), and extracted with and EA (150 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA =20:1-5:1 as the eluent to give 528-5 (8.02 g. 88%).

[1121] To a solution of 528-5 (8.02 g, 22.6 mmol) and Boc₂O (14.8 g, 67.77 mmol) in MeOH (100 mL) was added Pd/C (3.0 g. 10%) under N₂. The suspension was degassed and purged with H₂ for several times. The mixture was stirred under H₂ balloon at 25 °C for 3 h. TLC showed that the starting material was consumed completely. The mixture was filtered through a pad of Celite. and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=50:l~5:l) to give 5286 (5.5 g). +EST-MS: m/z 428.9 [M+H]⁺.

[1122] 528-13 (white solid. 80 mg) was prepared following the general procedure for preparing 272 using 528-6. +ESI-MS: m/z 712.1 [M+H] .

[1123] To a solution of 528-13 (80.00 mg crude) in a co-solvent of MeOH (5 mL) and THE (5 mL) was added NaBHi (40 mg, 1.05 mmol), and the mixture was stirred at 25 °C for 2 h. The reaction was quenched by H₂O and extracted by EA (10 mL x 3). The combined

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PCT/US2014/051642 organic layers were washed with brine, dried over anhydrous +028()4 and concentrated at low pressure. The residue w^ras purified by prep-TLC to give 528-14 (51 mg). +ES1-MS: m/z

684.1 [M+H]⁺.

[1124] Compound 528 (white solid. 18 mg. 39.9%) was prepared following the general procedure for preparing 272 using 528-14. +EST-MS: m/z 584.0 [M+H]⁺.

EXAMPLE 298

Preparation of Compound 529 o'

[1125] To a solution of 529-1 (150.00 mg) in MeOH (50 mL) was added RaNi (0.15 g) under N₂. The suspension was degassed and purged with H₂ for several times. The mixture was stirred under H? balloon at 25 °C for 2 H. TLC (PE:EA=1:1) showed that the starting material was consumed. The mixture was filtered, and the filtrate was concentrated to give 529-2 (90 mg. crude), which was used directly without further purification.

[1126] Compound 529 (white solid, 13 mg) was prepared following the general procedure for preparing 528 by using 529-2. +EST-MS: m/z 550.1 [M+H]⁺.

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EXAMPLE 299

Preparation of Compound 532

[1127] Compound 532 (white solid, 13 mg) was prepared following the general procedure for preparing 501 and 272 by using 532-1. +ES1-MS: m/z 597.1 [M+H]⁺.

EXAMPLE 300

Preparation of Compound 533

O'

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PCT/US2014/051642 [1128] To a solution of 533-1 (10 g, 31.9 mmol) in anhydrous THF (100 mL) was added LillMDS (63.9 mL, 63.9 mmol) dropwise, and stirred at -78 °C for 30 mins. A solution of Mel (9.07 g, 63.9 mmol) in dry THF (50 mL) was added dropwise. The mixture was warmed to 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with water (100 mL) and extracted with EA (150 mL x 3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=T0:l) to yield 533-2 (3.5 g. 32%) as a light yellow solid.

[1129] 533-4 (crude, yellow⁷ oil) w⁷as prepared fol lowing the general procedure for preparing 501 by using 2. +ESI-MS: m/z 369.0 [M+H]⁺.

[1130] To a solution of 533-4 (500.00 mg, 1.35 mmol) in MeOH (30 mL) w⁷as added SnCl₂ · 2II₂O (760.40 mg. 3.39 mmol) in one portion at r.t. under N?. and the mixture was stirred for 2 h. TLC showed that the reaction was completed. The mixture was diluted with water (20 mL). The solution was extracted with EA (30 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO4, and concentrated under reduced pressure. The residue was used in the next step without purification.

|1131] To a solution of 533-5 (0.5 g, 1.46 mmol) and CbzCl (745.56 mg. 4.37 mmol) in DCM (15 mL) was added NaHCCf (489.61 mg. 5.83 mmol) in one portion, and the mixture w^ras stirred at r.t. for 1 h. The solution was poured into ice-water (15 mL) and stirred for 20 mins. The aqueous phase was extracted with EA (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA=30:1-10:1) to afford 533-6 (0.4 g) as a yellow solid. +ESI-MS: m/z 477.1 [M+H]⁺.

[1132] To a solution of 533-6 (0.4 g, 0.84 mol) in THF (40 mL) was added LiBH₄(55 mg, 2.5 mmol) in one portion, and the mixture stirred at r.t. for 1 h. TLC showed that the reaction was completed. The mixture was poured into ice-water (15 mL) and stirred for 20 mins. The aqueous phase was extracted with EA (40 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄. filtered and concentrated at low pressure. The residue w⁷as purified by column chromatography (PE:EA=30:l~2:l) to afford 533-7 (320.00 mg, 85%) as a yellow solid. +ESI-MS: m/z 448.6 [M+H]⁺.

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PCT/US2014/051642 [1133] To a solution of 533-7 (320 mg, 0.71 mmol) in DME (5 mL) and H?O (1 mL) were added 4.4,6-trimethyl-2-[l-(trifluoromethyl)vinyl]-l,3,2-dioxaborinane (320 mg, 1.42 mmol), CS2CO3 (0.7 g, 2.13 mmol), and Pd(dppf)CE (52 mg, 0.07mol) under Nt. The reaction flask was sealed and stirred at 110 °C by microwave irradiation for 1 h. The reaction was cooled to r.t., and diluted with EA and water. The organic phase was washed with brine, dried over anhydrous Na;SO| and concentrated under reduced pressure. The residue was purified by column chromatography using 3-20% of EA in PE as the eluent to give 533-8 (220 mg, 60%). +ESI-MS: m/z 508.9 [M+H]⁺.

[1134] To a mixture of 533-8 (100.00 mg, 0.2 mmol) in t-BuOH (1.5 mL) and LEO (0.5 mL), were added K2OSO4H2O (11 mg. 0.06 mmol) and BocHN-OTs (113 mg. 0.39 mmol), and the mixture was stirred at r.t. overnight. The mixture was poured into ice-water, stirred for 20 mins and extracted with EA (10 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4. filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:1-20:1 as the eluent to give 533-9 (50 mg, 40%) as a yellow solid. +ESI-MS: m/z 642.1 [M+H]⁺.

[1135] To a solution of 533-9 (50.00 mg, 0.078 mmol) in DCM (2 mL) was added TFA (1 mL). The mixture was stirred at r.t. for 1 h. The solution was poured into ice-water (5 mL) and neutralized with sat. NallCOj solution. The aqueous phase was extracted with EA (5 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using EA as the eluent to give 533-10 (30.00 mg, 71%) as a yellow solid. +EST-MS: m/z 542.1 [M+H]⁺.

[1136] 533-11 (yellow solid, 30 mg, 74%) was prepared following the general procedure for preparing 272 using 533-11. +ESI-MS: m/z 732.3 [M+H] .

[1137] To a solution of 533-11 (30 mg) in CH3CN (1 mL) was added one drop of TMSI at r.t. The mixture was stirred at r.t. for 10 mins. The mixture was poured into water, neutralized with sat. NaHCOj solution and extracted with EA (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 533 (23.00 mg) as a while solid. +ES1-MS: m/z 597.9 [M+H]^-.

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EXAMPLE 301

Preparation of Compound 534

[1138] Lo a solution of 534-1 (6 g. 18.3 mmol) and TEA (18.5 g, 183 mmol) in THF (60 mL) was added aq. HCHO (15 g. 183 mmol) at 25 °C under N₂. The mixture was stirred at 25 °C for 2 h. TLC (PE:EA=5:1) showed that the reaction was completed. The mixture was diluted with water and extracted with EA (100 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:1-5:1 as the eluent to afford 534-2 (5.1 g, 77%) as a white oil. +ES1-MS: m/z 358.1 [M+H]⁺.

[1139] To a solution of 534-2 (1.76 g. 4.91 mmol) in DCM (20 mL) was added DAST (7.91 g. 49.10 mmol) dropwise at -78 °C under N₂. The mixture was slowly warmed to 25 °C. and stirred for 12 h. TLC (PE:EA=5:1) showed that the reaction was completed. The mixture was cooled to 0 °C and quenched with sat. NaHCO₃ solution. The aqueous phase was extracted with EA (20 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated at low pressure. The residue was purified by column chromatography using PE:EA=100:l~ 60:1 as the eluent to afford 534-3 (0.6 g. 34%) as a white oil. +ESI-MS: m/z 360.1 [M+H]⁺.

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PCT/US2014/051642 [1140] To a solution of 534-3 (590 mg, 1.64 mmol) in MeOH (6 mL) was added a solution of NaOH (260 mg, 6.6 mmol) in ILO (6 mL) at r.t. The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to r.t., and the organic solvent was removed under reduced pressure. The pH of aqueous phase was adjusted to ~3 using 2M HC1 and extracted with EA (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated in vacuum to give 534-4 (503 mg, 88%) as a white solid.

[Π41] To a solution of 534-4 (438 mg, 1.27 mmol), DIPEA (655 mg, 5.07 mmol) and BnOH (274 mg, 2.53 mmol) in toluene (5 mL) was added DPPA (698 mg, 2.54 mmol) at r.t. under N₂. The mixture was heated to 80 °C and stirred for 12 h. The mixture was cooled to r.t. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:1-5:1 as the eluent to afford 534-5 (450.00 mg. 78.52%) as a white solid.

[1142] Compound 534 (white solid, 21 mg, 45.9%) was prepared following the general procedure for preparing 533 using 534-5. +ESI-MS: m/z 600.0 [M+H]⁺.

EXAMPLE 302

Preparation of Compound 535

/°

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PCT/US2014/051642 [1143] To a solution of 535-1 (2.0 g, 4.2 mmol) in MeOH (20 mL) was added NaBIIj (476 mg, 12.6 mmol) at r.t. in small portions. Lhe solution was stirred for 30 mins and quenched with ILO. Lhe mixture was extracted with EA (50 mL). The organic phase was washed with brine, dried over anhydrous N/bSCL. fdtered and concentrated in vacuum. The residue was purified by column chromatography using PE:EA=1:1 to give 535-2 (1.6 g. 85%) as a white solid. +ESI-MS: m/z 449.1 [M+H]⁺.

[1144] To a solution of535-2 (1.40 g, 3.1 mmol) in THF (20 mL) were added Ag2O (723 mg, 3.1 mmol) and Mel (1.77 g, 12.5 mmol) at r.t. Lhe mixture was sealed and heated to 40 °C. The reaction was stirred overnight and concentrated to dryness at low pressure. The residue was purified by column chromatography using PE:EA=10:l as the eluent to give 535-3 (450 mg, 31%). +ESI-MS: m/z 463.1 [M+H]⁺.

[1145] Compound 535 (white solid, 11 mg, 22%) was prepared following the general procedure for preparing 533 using 535-3. +ESI-MS: m/z 612.1 [M+H]⁺.

EXAMPLE 303

(A

o [1146] Compound 536 (white solid, 65 mg. 83%) was prepared following the general procedure for preparing 533 and 501 using 536-1. +ES1-MS: m/z 611.2 [M+H]⁺.

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EXAMPLE 304

Preparation of Compound 537

[1147] To a solution of 537-1 (0.7 g, 2.1 mmol) in THF (8 mL) was added LiHMDS (3.2 mL 1 M in THF) at -78 °C in a period of 1 minute under Nj. After stirring at 78°C for 10 minutes, a solution of M0MC1 (340 mg. 4.2 mmol) in THF (2 mL) was added at -78 °C in a period of 1 min under Nt. The reaction mixture was wanned to room temperature and stirred for 20 minutes. LCMS showed that 537-1 was consumed completely. The reaction was quenched by water and extracted with EA (20 mL X 3). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to give 537-2 (720 mg, 82%) as colorless oil. +ESI-MS: m/z 372.1 [M+H]⁺.

[1148] 537-8 (white solid. 45 mg. 78%) was prepared following the general procedure for preparing 533 using 537-2. +ESI-MS: m/z 746.1 [M+H]⁺.

[1149] To a solution of 537-8 (45 mg, 0.06 mmol) in TFA (1 ml,) was added HBr/HOAc (1 mL, 40%) at r.t. The reaction mixture was stirred at room temperature until all starting material w^zas consumed (followed bv LCMS). The resulting mixture was concentrated under reduced pressure. The residue was neutralized with aqueous NaHCO? and

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PCT/US2014/051642 extracted with EA. The combined organic phase was concentrated under reduced pressure.

The residue was purified by Pre-IIPLC to afford 537 (9 mg. 16.3%) as a white solid. +ESIMS: m/z 654.1 [M+H]⁺.

EXAMPLE 305

Preparation of Compound 540

[1150] Compound 540 (white solid, 175 mg, 71%) was prepared following the general procedure for preparing 534 using 540-1. +ES1-MS: m/z 604.1 [M+H]⁺.

EXAMPLE 306

Preparation of Compound 541

[1151] Compound 541 (white solid. 13 mg. 18.4%) was prepared following the general procedure for preparing 537 and 528 using 541-1. +EST-MS: m/z616.0 [M+H]⁺.

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EXAMPLE 307

Preparation of Compound 544

544-9 544-10 [1152] To a solution of CIIjCN (24.6 g, 600 mmol) in toluene (200 mL) was added n-BuLi (120 mL, 2.5 M in hexane) dropwise at -78°C under N₂. The mixture was stirred at -78 °C for 30 mins. The mixture was treated with a solution of 544-1 (36.0 g, 120 mmol) in toluene (200 mL). The mixture was warmed to r.t. and stirred for 2 h. The reaction was quenched with sat. aq. NH4CI, and extracted with EA (4 x 200 mL). The combined organic layer w^ras washed with brine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified by column chromatography to give 544-2 as a white solid (31.5 g, 85.0%). +ESI-MS: m/z 308.9 [M+H]⁺.

[1153] To a solution of 544-2 (30.9 g. 100 mmol) in MeOH (600 mL) was added NaBH₄ (19 g, 500 mmol) in portions at 0 °C, and stirred at 0 C for 4 h. The mixture was quenched with water, and extracted with EA (4 x 300 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO₄. filtered and concentrated under reduced pressure. The residue was further purified by column chromatography to afford 544-3 as a light yellow solid (28.0 g. 90.0%). +ESI-MS; m/z 310.9 [M+H]⁺.

[1154] To a solution of 544-3 (5 g, 16.08 mmol) in MeOH (100 mL) was added SOCL (20 mL) at 0 °C dropwise. The mixture was heated to reflux and stirred for 48 h. The

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PCT/US2014/051642 mixture was cooled to r.t. The solution was neutralized with sat. aq. NaHCO₃, and extracted with EA (4 x 300 mL). The combined organic layer was washed with brine, dried over anhydrous NajSCfi, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 544-4 as a light yellow solid (3.32 g. 60.0%).

[1155] Compound 544-5 (light yellow solid, 2.65 g, 90%) was prepared was prepared following the general procedure for preparing 544-3 using 544-4. +ESI-MS: m/z 315.7 [M+H]⁺.

[1156] To a solution of 544-5 (2.65 g. 8.38 mmol) and TEA (2.54 g, 25.15 mmol) in DCM (20 mL) was added MsCl (2.88 g, 25.15 mmol) at 0 °C. The mixture was stirred at r.t. for 2 h. The reaction was quenched with sat. aq. \al ICC)_; and extracted with EA (4 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated at low pressure. The residue was purified by column chromatography to afford 544-6 as a light yellow solid (3.2 g. 80.8 %).

11157] To a solution of 544-6 (3.2 g, 8.4 mmol) in toluene (50 mL) were added BnNH₂ (5.4 g, 50.3 mmol), K₂CO₃ (6.9 g, 50.3 mmol), and KI (100 mg) at r.t. The mixture was stirred at 160 °C for 6 h. The mixture was cooled to r.t. and diluted with water. The solution was extracted with EA (4 x 100 mL). The combined organic layer was washed with brine, dried over anhydrous Na₂SO4, filtered and concentrated at low pressure. The residue was purified by column chromatography to afford 544-7 as a light yellow solid (1.1 g, 33.9%). +ESI-MS: m/z 386.9 [M+H]⁺.

[1158] Compound 544 (white solid, 450 mg, 40.3%) was prepared was prepared following the general procedure for preparing 528 using 544-7. +ESI-MS: m/z 670.3 [M+H]⁺.

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EXAMPLE 308

Preparation of Compounds 545 and 546

[1159] Compounds 545 (white solid, 112 mg) and 546 (white solid, 107 mg) was prepared following the general procedure for preparing 495 and 496 using 545-1 and 545-2. 545: +ESI-MS: m/z 566.2 [M+H]⁺; and 546: +ESI-MS: m/z 566.2 [M+H]⁺.

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EXAMPLE 309

Preparation of Compounds 547 and 548 o

[1160] Compounds 547 (white solid. 45 mg) and 548 (white solid, 48 mg) was prepared following the general procedure for preparing 271 and 272 using 547-1 and 547-2. 547: +ESI-MS: m/z 599.1 |M+H]⁺; and 548: +ES1-MS: m/z 599.1 [M+H]⁺.

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EXAMPLE 310

Preparation of Compounds 549 and 550

[1161] Compounds 549 (white solid. 102 mg) and 550 (white solid, 108 mg) was prepared following the general procedure for preparing 271 and 272 using 549-1 and 549-2. 549: +ESI-MS: m/z 585.9 [M+H]⁺; and 550: +ESI-MS: m/z 586.0 [M+H]⁺.

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EXAMPLE 311

Preparation of Compounds 551 and 552

OH 0

NH₂-HCI [1162] Compounds 551 (white solid. 78 mg) and 552 (white solid, 72 mg) was prepared following the general procedure for preparing 271 and 272 using 551-1 and 551-2. 551: +ESI-MS: m/z 600.2 [M+H]⁺; and 552: +ES1-MS: m/z 600.2 [M+H]⁺.

EXAMPLE 312

Preparation of Compounds 553 and 554

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PCT/US2014/051642 [1163] Compounds 553 (white solid, 35 mg) and 554 (white solid, 45 mg) was prepared following the general procedure for preparing 495 and 496 using 553-1 and 553-2. 553: +ESI-MS: m/z 552.2 |M+H]¹; and 554: +ES1-MS: m/z 552.1 [M+H]\

EXAMPLE 313

Preparation of Compound 555

[1164] To a solution of 555-1 (2.74 g, 10 mmol) in anhydrous THF (30 mL) was added w-BuLi (4.8 mL. 2.5 M in hexane) dropwise at -78 °C under N?. The mixture was stirred at -78 °C for 20 mins, and then treated with a solution of tcrt-butyl 3-oxoazetidine-lcarboxylate (1.71 g, 10.00 mmol) in anhydrous THF (5 mL) at -78 °C. The solution was stirred for 30 mins at -78 °C. The reaction was quenched with water and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4, fdtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=9:1 as the eluent to afford 555-2 (1.05 g, 33%). +ESIMS: m/z 319.1 [M+H]⁺.

[1165] To a solution of 555-2 (0.8 g. 2.52 mmol) and (3-chloro-4-fluorophenyl) boronic acid (440 mg, 2.52 mmol) in dioxane:! LO (10:1 mL) were added CS2CO3 (1.23 g, 3.78 mmol) and Pd(dppf)C12 (185.00 mg. 0.25 mmol) under N₂. The mixture was heated to

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PCT/US2014/051642 °C in an oil bath and stirred for 1 h. The mixture was cooled to r.t., poured into H₂O (20 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=9:1 as the eluent to afford 555-3 (780 mg). +ESI-MS: m/z 413.1 [M+H]⁺.

[1166] To a solution of 555-3 (780 mg, 1.89 mmol) in DCM (8 mL) was added TFA (2 mL). and the mixture stirred at r.t. for 30 mins. The mixture was concentrated under reduced pressure, and the residue was dissolved in DCM (10 mL) and Et₂N (572 mg, 5.65 mmol). CbzCl (643 mg. 3.77 mmol) was added slowly at r.t.. and the mixture was stirred for 2 h. The solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduce pressure. The residue was purified by column chromatography using PE:EA=4:1 as the eluent to give 555-5 (720.00 mg). +ESI-MS: m/z 447.1 [M +H]⁺.

[1167] Compound 555 (white solid, 3.5 mg. 16.3%) was prepared following the general procedure for preparing 533 using 555-5. +ESI-MS: m/z 595.9[M+H]⁺.

EXAMPLE 314

Preparation of Compounds 561 and 562

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PCT/US2014/051642 [1168] Compounds 561 (white solid, 50 mg) and 562 (white solid, 48 mg) was prepared following the general procedure for preparing 495 and 496 using 561-1 and 561-2. 561: +ESI-MS: m/z 565.1 [M+HJ¹: and 562: +ESI-MS: m/z 565.1 [M+H]\

EXAMPLE 315

Preparation of Compound 563

	F
^Cl,+ H I	ΌΙ ^C!	N ,¼. i ' I '	II	Cl	ί i	Cl	Ck	..α·Α⁷·Α	'Cl
		Μ o			o			T O
563-1		A. s ' N 563-2			ηΎ 563-3		HO^	563-4

563-5

[1169] A solution of 563-1 (3.00 g, 10.56 mmol) and tetraethoxytitanium (7.23 g, 31.68 mmol) in anhydrous THF (60 mL) was stirred for 5 mins. The solution was treated with 2-methylpropane-2-sulfinamide (1.92 g, 15.84 mmol) and stirred at 70 °C for 5 h. The mixture was cooled to r.t., and the reaction w*as quenched with sat. aq. NaHCCf until white titanium salts precipitate was formed. The suspension was filtered through a pad of Celite. and the cake was washed with EA. The aqueous w'as extracted with EA. The combined organic layers were washed with brine, dried over anhydrous Na2SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give 563-2 (3.50 g, 85.6%). +ES1-MS: m/z 387.0 [M+H]⁺.

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PCT/US2014/051642 [1170] To a solution of 563-2 (3.50 g, 9.0 mmol) in anhydrous THF (15 mL) was added allylmagnesium bromide (13.6 mL, 1.0 M in THF) at -78 °C under N₂, and the mixture was stirred at -78 °C for 1 h. The mixture was allowed to warm to 25 °C and stirred for another 1 h. The reaction was quenched with aq. NH4CI solution and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4. fdtered and concentrated under reduced pressure. The residue was purified column chromatography to afford 563-3 (1.20 g. 31%) as a yellow solid. +ESI-MS: m/z 429.1 [M+H]⁺.

[1171] Ozone was bubbled into a solution of563-3 (1.2 g, 2.8 mmol) in anhydrous MeOH (30 mL) at -78 °C for 10 mins. After excess O₃ w⁷as purged by nitrogen, NaBHj (420 mg 11.2 mmol) was added at 25 °C in portions. The solution was stirred for 30 mins at r.t. The reaction was quenched with H₂O and extracted with EA (3 x 60 mL). The combined organic layers were washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue w⁷as purified by column chromatography using PE:EA = 2:1 as the eluent to give 563-4 (1.02 g. 83%) as a solid. +ES1-MS: m/z 433.1 [M+H]⁺.

[1172] To a solution of 563-4 (1.01 g, 2.5 mmol) and PPh₃ (1.0 g, 3.8 mmol) in anhydrous TI IF (20 mL) was added DIAD (870 mg, 4.3 mmol) dropwise at 25 C under N₂. The mixture was heated to 70 C and stirred for 4 h. The mixture was cooled to 25 °C and concentrated under reduced pressure. The residue was purified by column chromatography to afford 563-5 (902 mg, 85%) as a solid.

[1173] To a solution of 563-5 (902 mg 2.2 mmol) in dioxane (8 mL) was added cone. HCI (1 mL, 12 M) in one portion, and stirred at 25 C for 1 h. The mixture was concentrated to give 563-6 (750 mg), which was used for the next step without further purification.

[1174] 563-6 (750mg) and NaHCO₃ (607 mg, 7.2mmol) were dissolved in DCM (10 mL) and H₂O (1 mL). The solution was treated with CbzCl (617 mg 3.6 mmol) at r.t. The mixture w⁷as stirred at r.t. for 1 h. The mixture was diluted w⁷ith water and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous η O >

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Na^SO-i, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 563-7 (990 mg, 93%). +ESI-MS: m/z 444.9 [M+I I]'.

[1175] 563-8 (white solid, 1.1 g, 16.3%) was prepared following the general procedure for preparing 533 using 563-7. +ES1-MS: m/z 595.9 [M+H]⁺. 563-9 (402 mg) was obtained by SFC separation of 563-8 (1.1 g).

[1176] Compound 563 (white solid. 20 mg, 33%) was prepared following the general procedure for preparing 533 using 563-9. +ESI-MS: m/z 593.9 [M+H]⁺.

EXAMPLE 316

Preparation of Compound 564

564-3

O

[1177] 564-3 was prepared as described in Franck, D. et al.. Bioorganic &

Medicinal Chemistry (2013) 21(3):643-652.

[1178] To a solution of 564-4 (11.22 g. 35.7 mmol) in anhydrous THF (200 mL) was added LiHMDS (286 mL 1 M in THF) in portions at -78 °C under N₂. The mixture was stirred at -78 °C for 30 mins. The mixture was treated with a solution of 564-3 (22 g, 71.4 mmol) in anhydrous THF (50 mL) dropwise. The mixture was warmed to r.t. and stirred for 3 h. The reaction was quenched with ice-water (150 mL). The aqueous phase was extracted with EA (3 x 200 mL). The combined organic phase was washed with brine, dried over anhydrous NasSCfi and concentrated under reduced pressure. The residue was purified

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PCT/US2014/051642 by column chromatography using PE:EA=30:l~10:l as the eluent to afford 564-5 (11.0 g,

70% purity) as a light yellow oil. +ESI-MS: m/z 460.0 [M+I I]^h.

[1179] To a solution of 564-5 (11.0 g, 23.9 mmol) in anhydrous THF (60 mL) was added LiAlH4 (907 mg, 23.9 mmol) in portions at 0 °C under N₂. The mixture was stirred at 0 °C for 30 mins. The reaction was quenched by ice-water and filtered via a pad of Celite. The filtrate was extracted with EA (3 x 100 mL). The combined organic phase was washed with brine, dried with anhydrous Na₂SC>4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:1-20:1 as the eluent to afford 564-6 (3.8 g, 28% yield, 81% purity) as a light yellow oil. +F.SI-MS: m/z 432.1 [M+H]⁺.

[1180] To a solution of 564-6 (0.8 g, 2.34 mmol) and TEA (0.71 g, 7.01 mmol) in DCM (10 mL) was added MSC1 (270 mg, 2.34 mmol) dropwise at 0 °C, and the mixture was stirred at 20 °C for 30 mins. The mixture was poured into ice-water (50 mL) and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried with anhydrous Na2SO₄, filtered and concentrated under reduced pressure to afford 564-7 (0.6 g, crude) as a yellow oil. which was used lor next step directly. +ES1-MS: m/z 509.9 [M+H]⁺.

[1181] To a solution of crude 564-7 (0.6 g, 1.43 mmol,) in DMSO (6 mL) was added NaBfL (270 mg, 7.14 mmol) in one portion at r.t. under N₂. The mixture was stirred at 50-60 °C for 12 h. The reaction was cooled to r.t., quenched with ice-water and extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried with anhydrous Na₂SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:l~8:l as the eluent to afford 564-8 (0.3 g, 78% purity) as a yellow solid. +ESI-MS: m/z 415.9 [M+H]⁺.

[1182] Compound 564 (white solid. 2.7 mg) was prepared following the general procedure for preparing 533 using 564-8. +ESI-MS: m/z 609.1 [M+H]⁺.

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EXAMPLE 317

Preparation of Compound 569

[1183] Compound 569 (white solid. 53 mg, 74%) was prepared following the general procedure for preparing 495 using 569-1 and 569-2. +ESI-MS: m/z 519.1 [M+H]⁺.

EXAMPLE 318

Preparation of Compound 570

[1184] Compound 570 (white solid, 25 mg, 32%) was prepared following the general procedure for preparing 495 using 570-1 and 570-2. +ESI-MS: m/z 517.1 [M+H]⁺.

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EXAMPLE 319

Preparation of Compound 571

nh₂- hci [1185] Compound 571 (white solid, 21 mg. 23%) was prepared following the general procedure for preparing 495 using 571-1 and 571-2. +ESI-MS: m/z 517.1 [M+H]⁺.

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EXAMPLE 320

Preparation of Compounds 604a-d

OH OH OH

CIHH₂N [1186] To a mixture of 604-1 (12.0 g, 92.6 mmol) and 2,2.2-trifluoroethane-l,ldiol (32.3 g, 277.9 mmol) in H₂O (25 mL) was added K₂CO₃ (25.6 g. 185.2 mmol, 2.00 eq.) in one portion at r.t. The flask was sealed, heated to 125°C and stirred for 16 h. The mixture

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PCT/US2014/051642 was cooled to 0 °C, neutralized with IM HCI solution, and extracted with EA (3 x 100 mL).

The combined organic phase was dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was washed with DCM and PE to afford 604-2 (17.0 g,

%) as a white solid.

[1187] To a stirring solution of 604-2 (130 g, 571.2 mmol) and Na₂CO₃ (121 g. 1.1 mol) in H₂O (800 mL) was added I₂ (174 g. 685.5 mmol) in portions. The mixture was stirred at 25 °C for 48 h. A sat. sodium sulfite solution (500 mL) was used to quench the reaction. The mixture was acidified with 3M HCI and diluted with EA (1 L). The organic phase whs separated, and the aqueous phase was extracted with EA (3 x 500 mL). The combined organic phase was dried over anhydrous Na₂SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography by using PE:EA=1:1 as the eluent to afford 604-3 (180 g, 89%) as a white solid.

[1188] To a solution of 604-3 (88 g, 249 mmol) and 1 -chloropropan-2-one (55.9 g. 605.0 mmol) in DMF (200 mL) was added NaHCO₃ (62.7 g, 746.1 mmol) in one portion at r.t. under N₂. Lhe mixture was stirred at 25 °C for 25 h. and the solid w^ras removed by filtration. The filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in DCM and triturated with PE to afford 604-4 (66 g, 65%) as a white solid.

[1189] A mixture of 604-4 (9.0 g, 22 mmol), 2-methylpropane-2-sulfinamide (Sconfiguration. 2.66 g, 22 mmol) and titanium(IV) ethoxide (10.5 g, 46.1 mmol) in anhydrous THF (18.00 mL) was heated to 80 °C (sealed vial, degassed and purged with N?) and stirred for 1 h. EA (150 mL) and water (10 mL) were added with stirring. Lhe mixture was stirred for 5 mins and filtered through a pad of celite. The filtrate was concentrated under reduced pressure, and the residue w⁷as purified by column chromatography on silica gel using EA:DCM=1:9 as the eluent to afford 604-5 (6.8 g. 60%).

[1190] To a solution of EtMgBr (4.4 mL. 13.2 mmol, 3 M in ether) in dry⁷ THF (50 mL) w⁷as added w-BuLi (10.6 mL, 26.5 mmol, 2.5 M in hexane), and the mixture w⁷as stirred at 0 °C. After stirring for 10 mins, the mixture was cooled down to -78 °C. A solution of 604-5 (6.8 g, 13.26 mmol) in dry THF (50 mL) w⁷as added dropwise, and the reaction was stirred at -78 °C for 15 mins. The reaction was quenched with H₂O (50 mL) and extracted with EA (2 x 100 mL). The combined organic phase was washed with brine, dried

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PCT/US2014/051642 over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 0-10% EA in DCM) to afford 604-6 (3.10 g, 60%).

[1191] To a stirring solution of 604-6 (6.8, 17.6 mmol) in DCM (50 mL) was added Dess-Martin reagent (8.95 g, 21.1 mmol), and the mixture was stirred at r.t. under N2 for 1 h. The reaction was quenched with sat. aq. NajSCb solution and sat. aq. NallCOj solution. After 30 mins of stirring vigorously, the organic layers were separated, and the aqueous layer was extracted with ΕΛ (2 x 100 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 0-10% EA in DCM) to afford 604-7 (5.1 g 75.4%).

[1192] To a solution of /-BuOK (1.64 g, 14.58 mmol) in CH3CN (150 mL) was added Mc;S()I (3.21 g, 14.58 mmol). The mixture was degassed and stirred at r.t. for 30 mins. The solution containing the ylide was filtered from the solid and added to a solution of 604-7 (5.1 g, 13.25 mmol) in CHjCN (150 mL), which had been previously degassed. The reaction was stirred at r.t. for 1 h. The volatiles were removed under reduced pressure. The residue was purified by column chromatography using DCM:EA=9:1 as the eluent to give 604-8 (3.2 g, 60.5%).

[1193] To a solution of 604-8 (3.2 g, 8.02 mmol) in MeOH (300 mL) was added ammonia water (10 mL) in one portion. The solution w^ras stirred at 25 °C for 18 h. The volatiles were removed under reduced pressure to afford crude 604-9 (3.1 g, 93%).

[1194] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (460 mg, 2.17 mmol) in DCM (6 mL) was added IIATU (985 mg, 2.59 mmol) and DIPEA (558 mg, 4.32 mmol) in one portion at r.t. After stirring for 10 mins, 604-9 (900 mg, 2.16 mmol) was added. The mixture was stirred for I h at r.t. The solution was washed with brine, dried over anhydrous l^SCfi, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 10-100% EA in PE) to give 604-10 (890 mg. 67.5%).

[1195] 604-10 (300 mg, 0.49 mmol). (4-cyanophenyl)boronic acid (88 mg, 0.6 mmol) and CS2CO3 (240 mg, 0.74 mmol) were taken up into a microwave tube in co-solvent

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DME:H₂O (12 mL, v:v=5:l). The solution was degassed and Pd(PPh₃)4 (57 mg, 0.05 mmol, 0.10 eq.) was added. The sealed tube w^fas heated to 110 °C by microwave irradiation and stirred for 1 h. The solution was cooled to r.t. and poured into water. The mixture was extracted with EA (2 x 20 mL). The combined organic layers were washed with brine (20 mL). dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using EA as the eluent to give 604-11 (320 mg. 96.2%).

[1196] To a solution of 604-11 (300 mg, 0.44 mmol) in dioxane (3 mL) was added ElCl/dioxane (1 mL, 4M) at r.t. The mixture was stirred at r.t. until all the starting material w as consumed. The mixture was concentrated under reduced pressure. The residue was dissolved in EA, and basified by a sat. NaHCCf solution. The organic phase was washed with brine, dried over anhydrous Na₂SC>4, filtered and concentrated under reduced pressure to afford crude 604-12 (-200 mg, 71% yield, 90% purity).

[1197] 604-12 (-200.00 mg, 90% purity) was separated by SFC (Column:

Chiralcel OJ-H 250x4.6mm I.D., 5um Mobile phase: methanol (0.05% DEA) in CO2 from5% to 40% Flow rate: 2.35mL/min Wavelength: 220nm) to give peak 1, peak 2, peak 3 and peak 4. The solution of peak 1 in CH₃CN and water was treated with HC1 (2 M, 0.2 mL) and lyophilized to give 604a (25 mg). +ESI-MS: m/z 573.1 [M+I I], The solution of peak 2 in CH₃CN and water was treated with HC1 (2 M, 0.2 mL) and lyophilized to give 604b (25 mg). +ESI-MS: m/z 573.1 [M+H]⁺ The solution of peak 3 in CH3CN and water was treated with HC1 (2 M. 0.2 mL) and lyophilized to give 604c (19 mg). +ESI-MS: m/z 573.1 [M+H]⁺. The solution of peak 4 in CH3CN and water was treated with HC1 (2 M. 0.2 mL) and lyophilized to give 604d (22 mg). +ES1-MS: m/z 573.3 [M+H]⁺

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EXAMPLE 321

Preparation of Compounds 605a-d

[1198] To a solution of 604-10 (400 mg, 0.66 mmol) and (4-fluorophenyl)boronic acid (138 mg. 984 mmol) in DME (3 mL) and LEO (1 mL) was added Pd(dppf)Cl₂ (24 mg. 0.033 mmol) and Cs₂CC>3 (641 mg, 2.0 mmol) in a micro wave tube under N₂. The reaction mixture was heated to 100 °C and stirred for 1 hour. After cooling to room temperature, the reaction mixture was poured into water (30 mL) and stirred for 5 mins. The aqueous phase w'as extracted with EA (30 mL X 3). The combined organic phase was washed with brine, dried over anhydrous Na₂SC>4. filtered and concentrated under reduced pressure. The residue w'as purified by column chromatography using EA as eluent to give 605-1 (310 mg) as a white solid. +ESI-MS: m/z 670.1 [M +H]⁺.

[1199] Compounds 605a, 605b, 605c and 605d was prepared following the general procedure for preparing 605a using 605-1. The crude was purified by prep-HPLC

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PCT/US2014/051642 and SFC separation. 605a (white solid, 20 nig): m/z 566.2 [M+H]⁺, 605b (white solid, 18 mg): m/z 566.1 [M+H]⁺, 605c (white solid, 12.8 mg): m/z 566.1 [M+H]⁺ and 605d (white solid, 12.7 mg): m/z 566.2 [M+H]⁺.

EXAMPLE 322

Preparation of Compounds 629-632

[1200] Compounds 629, 630. 631 and 632 was prepared following the general procedure for preparing 605d using 604-10, 629-1 and (4-fluorophenyl)boronic acid. 629 (white solid, 14.1 mg): m/z 580.1 [M+H]⁺, 630 (white solid, 18.6 mg): m/z 580.1 [M+H]⁺, 631 (white solid, 25.8 mg): m/z 580.1 [M+H]⁺ and 632 (white solid, 34.5 mg): m/z 580.1 [M+H]⁺.

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EXAMPLE 323

Preparation of Compounds 633a-633b

[1201] 633-1 (9.0 g, 25.5 mmol) and Nal ICCL (6.4 g. 76.4 mmol) were dissolved in DMF (80 mL). 3-bromo-2-methylprop-l-ene (4.5 g. 33.1 mmol) was added by syringe, and the mixture was heated to 70 °C for 3 h. After cooling to r.t. the reaction was quenched with FLO and extracted with EA. The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (eluent: PE:EA = 30:1-8:1) to give 633-2 (8.02 g. 77%) as a white solid. +ESI-MS: m/z 407.8 [M+H]⁺.

[1202] A sealed tube was charged with a solution of 633-2 (7.0 g, 17.2 mmol) in toluene (50 mL). Pd₂(dba)₃ (580.0 mg. 1.0 mmol) and Q-phos (1.0 g, 1.4 mmol) was added under N₂. The sealed tube was stirred at 100 °C in an oil bath. After stirring for 7 h. the mixture was cooled to r.t. and concentrated at low pressure. The residue was purified by flash chromatography using 2-5% EA in PE as the eluent to afford 633-3 (3.5 g, 50%) as a solid.

[1203] To a solution of 633-3 (3.5 g, 8.6 mmol) in DMF (50 mL) was added NaN₃ (12.4 g. 190.7 mmol) at r.t. The solution was heated to 70 °C and stirred for 16 h. The

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PCT/US2014/051642 mixture was cooled to r.t. and quenched by pouring into water. The mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine, dried over anhydrous MgSO4. fdtered and concentrated under reduced pressure. The residue was purified by column chromatography using 5-12% EA in PE as the eluent to give 633-4 (2.4 g, 86.6%) as an oil. +ESI-MS: m/z 322.9 [M+H]⁺.

[1204] 633-8 was prepared following the general procedure for preparing 604a using 633-4.

[1205] 633-8 (500 mg. 0.92 mmol), (4-fluorophenyl)boronic acid (167 mg. 1.2 mmol), CS2CO3 (450 mg, 1.4 mmol) and Pd/PPtqfr (106 mg. 0.092 mmol) were taken up into a microwave tube in a co-solvent of dioxane (15 111L) and I EO (3 mL). Lhe sealed tube w as heated at 110 °C by microw-ave irradiation and stirred for 1 h. LCMS showed that -30% of the desired product was formed. Lhe solution was concentrated under reduced pressure, and the residue was purified by LLC and further purified by prep-HPLC to give pure 633a (-80 mg) and 633b (-70 mg). 633a: +ESI-MS: m/z 580.2 [M+H]⁺ and 633b: +ES1-MS: m/z 580.1 [M+H]⁺.

EXAMPLE 324

Preparation of Compound 638

nh₂-hci [1206] Compound 638 (white solid. 15 mg) was prepared following the general procedure for preparing 604a using 604-10 and (3-chloro-4-fluorophenyl)boronic acid. +ES1-MS: m/z 600.1 [M+H]⁺.

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EXAMPLE 325

Preparation of Compounds 653 and 654

OH

O

[1207] 2-chloro-4-iodo-6-(2,2,2-trifluoro-l-hydroxyethyl)pyridin-3-ol was prepared as provided in Henichart, J. et al., J. Het. Chem. (1986). 23(5):1531-1533.

[1208] To a solution of 2-chloro-4-iodo-6-(2,2.2-trifluoro-lhydroxyethyl)pyridin-3-ol (16 g. 45.3 mmol) in CHjCN (150 mL) was added K2CO3 (12.5 g. 90.5 mmol) in one portion. After stirring at r.t. for 5 mins, a solution of 653-3 (9.8 g, 54.3

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PCT/US2014/051642 mmol) in CH3CN (10 mL) was added slowly under N₂. The mixture was stirred at 90 °C for 1 h in a pre-heated oil bath. After cooling to r.t., the mixture was poured into water (150 mL) and stirred for 5 mins. The mixture was extracted with EA (2 x 150 mE). The combined organic phase was washed with brine, dried with anhydrous Na₂SO4, filtered and concentrated in vacuum. The residue was purified by column chromatography using 2-5% EA in PE as the eluent to afford 653-4 (10.9 g, 49%) as a yellow solid.

[1209] 653-8 was prepared following the general procedure for preparing 604a using 653-4.

[1210] To a solution of 653-8 (1.0 g, 1.9 mmol) in CH3NO2 (15 mL) was added TEA (2.0 mE) in one portion at r.t. The reaction mixture was stirred for 2 h and concentrated under reduced pressure. The residue was purified by column chromatography using 10-20% EA in PE as the eluent to afford 653-9 (0.8 g, 72%) as a yellow solid. +ESIMS: m/z 593.9 [M+H]⁺.

[1211] To a solution of 653-9 (400 mg, 0.67 mmol) in EtOH (10 mL) and H₂O (10 mL) was added Fe (188 mg, 3.4 mmol) powder and NH4CI (180 mg, 3.4 mmol) in one portion. The mixture was stirred at 80 °C for 2 h. After cooling to r.t., the mixture was poured into water (20 mL) and extracted with EA (3x10 mL). The combined organic phase was washed with brine, dried with anhydrous Na₂SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography using EA as the eluent to afford 653-10 (250 mg, 66%) as a yellow solid. +ESI-MS: m/z 564.1 [M+H]⁺.

[1212] To a solution of 4-cyclopropoxy-3-methoxybenzoic acid (75 mg, 0.36 mmol) in DMF (6.0 mL) was added HATU (137 mg, 0.36 mmol) and DTPEA (47 mg. 0.36 mmol). After stirring at r.t. for 5 mins, 653-10 (203 mg. 0.36 mmol) was added. The mixture was stirred for 1 h and then poured into water. The mixture was extracted with EA (2x10 mL). The combined organic phase was washed with brine, dried with anhydrous Na₂SC>4, filtered and concentrated in vacuum. The residue was purified by column chromatography using EA as the eluent to afford 653-11 (120 mg, 44.2 %) as a yellow solid. +ES1-MS: m/z 754.2 [M+H]⁺.

[1213] Ozone was bubbled into a solution of 653-11 (120 mg. 0.16 mmol) in anhydrous MeOH (10 mL) at -78 °C for 6 mins. After excess O3 was purged by N₂, Nall! I4

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PCT/US2014/051642 (18.1 mg, 0.48 mmol) was added at r.t. The reaction was stirred for 0.5 h and quenched with water. The mixture was extracted with EA (2 x 10 mL), dried over sodium sulfate, concentrated to give the crude product. The residue was purified by column chromatography using ΕΛ as the eluent to afford 653-12 (70 mg. 65%) as a yellow solid. +ESI-MS: m/z

682.1 [M+H]⁺.

[1214] To a solution of 653-12 (70 mg, 0.1 mmol) in MeOH (10 mL) was added HCl/dioxane (3 mL, 4 M). The mixture was stirred at r.t. for 20 mins. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC to afford 653 (12 mg) and 654 (18 mg) as white solids. 653: +ESI-MS: m/z 578.1 [M+H]⁺and 654: +ESIMS: m/z 578.1 [M+H]⁺.

EXAMPLE 326

Preparation of Compound 606

[1215] A mixture of 606-2 (45 mg. 0.1 mmol). 606-1 (16 mg, 0.1 mmol) and TEA (1 mmol) is dissolved in anhydrous DCM (4 mL) with stirring. The solution was treated with HATU (38 mg, 0.1 mmol) in one portion. After stirring at r.t. for 30 mins. TLA (1 mL) was added. The solution w^ras stirred at r.t. for 2 h. The mixture was concentrated to dryness. The residue was isolated by acidic prep-HPLC to afford 606 (26 mg, 45%) as a white solid. +ES1-MS: m/z 452.0 [M+H]⁺.

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EXAMPLE 327

Preparation of Compound 607

[1216] Compound 607 was prepared following the general procedure for preparing 606 using 607-1 and 606-2. The crude product was purified by prep-HPLC to give 607 (66 mg, 75%) as a white solid (oo iiyy ++). +ESI-MS: m/z 466.9 [M+H]⁺.

EXAMPLE 328

Preparation of Compound 608

608-1 η

[1217] Compound 608 was prepared following the general procedure for preparing 606 using 608-1 and 606-2. The crude product was purified by prep-HPLC to give 608 (46.5 mg, 84%) as a white solid. +ESI-MS: m/z 466.9 [M+H]⁺.

EXAMPLE 329

Preparation of Compound 609

[1218] Compound 609 was prepared following the general procedure for preparing 606 using 609-1 and 606-2. The crude product was purified by prep-HPLC to give 609 (13.5 mg, 34%) as a white solid. +ESI-MS: m/z 465.9 [M+H]⁺.

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EXAMPLE 330

Preparation of Compound 610

[1219] Compound 610 was prepared following the general procedure for preparing 606 using 610-1 and 606-2. The crude product was purified by prep-HPLC to give

610 (34 mg, 57%) as a white solid. +ESI-MS: m/z 518.9 [M+H]⁺.

EXAMPLE 331

Preparation of Compound 613

[1220] Compound 613 was prepared following the general procedure for preparing 606 using 613-1 and 606-2. The crude product was purified by prep-HPLC to give 613 (29 mg, 50%) as a white solid. +ESI-MS: m/z 451.9 [M+H]⁺.

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EXAMPLE 332

Preparation of Compounds 623a and 623b

[1221] To a solution of 623-1 (20 g, 116 mmol) in anhydrous toluene (200 mL) was added MeMgBr (3 Μ, 115.61 mL) slowly at 0°C under N₂. After addition and stirring for 30 mins, Ti(i-PrO)4 (36.1 g, 127.2 mmol) was added dropwise The mixture was heated at 100 °C for 30 mins. After cooling to r.t., copious quantities of diatomite was added to the mixture. The mixture was basified with aqueous NaOH solution (2 M) and filtered through a pad of diatomite. The cake w^ras washed with EA, and the filtrate was separated and concentrated to provide crude 2-(2.6-dichloro-4-pyridyl)propan-2-amine ( -25 g).

[1222] Crude 2-(2,6-dichloro-4-pyridyl)propan-2-amine was dissolved in anhydrous DCM (250 mL). The solution was treated with CbzCl (20.79 g, 121.90 mmol) and DIPEA (31.51 g, 243.80 mmol). The mixture was stirred at r.t. overnight. The mixture was wnshed with brine, dried over anhydrous Na>S()| and concentrated to dryness under reduced pressure. The residue was purified by column chromatography using 3-10%

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EA in PE as the eluent to give 623-2 (15 g, 36% yield over 3 steps) as a white solid. +ES1MS: m/z 338.8 [M+I I]⁺.

[1223] To a stirring solution of 623-2 (5.0 g, 14.7 mmol) in dioxane (100 mL) and water (10 mL) were added (4-cyanophenyl)boronic acid (2.17 g. 14.7 mmol). CS2CO3 (9.6 g. 29.5 mmol), and Pd(dppf)C12 (1.08 g. 1.47 mmol) under 1% The mixture was stirred at 80 °C for 1 h under N2. After cooling to r.t.. the mixture was diluted with EA (100 mL) and water (100 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated to dryness under reduced pressure. The residue w^ras purified by column chromatography using 3-20% EA in PE as the eluent to give 623-3 (2.0 g, 33% yield) as a white solid.

[1224] Compound 623-8 was prepared following the general procedure for preparing 533 using 623-3. Racemic 623-8 was separated by SFC and prep-HPLC to afford 623a (62 mg) and 623b (29 mg) as white solids. 623a: +ESI-MS: m/z 559.4 [M+H]⁺ and 623b: +ESI-MS: m/z 559.0 [M+H]⁺.

EXAMPLE 333

Preparation of Compounds 624a and 624b

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PCT/US2014/051642 [1225] Compounds 624a (white solid, 62 mg) and 624b (white solid, 62 mg) were prepared following the general procedure for preparing 623a and 623b using 624-1 and 6242. 624a: +ESI-MS: m/z 573.1 [M+H]^a and 624b: +ESI-MS: m/z 573.1 [M+H]⁺.

EXAMPLE 334

Preparation of Compound 625

[1226] Compound 625 (white solid. 32 mg) was prepared following the general procedure for preparing 623a and 623b using 625-1 and 624-2. +ESI-MS: m/z 572.1 [M+H]⁺.

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EXAMPLE 335

Preparation of Compound 634

[1227] Compound 634 (white solid, 10 mg) was prepared following the general procedure for preparing 406 using 634-1 and 634-2. +ESI-MS: m/z 524.1 [M+H]⁺.

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EXAMPLE 336

Preparation of Compound 639

[1228] 639-6 was prepared as provided in Pascal, R., et al., Eur. J. Org. Chem.

(2000) 2000(22):3755-3761.

[1229] To a solution of 639-6 (1.1 g, 5.3 mmol) in IfO (10 mL) was added NaOH (426 mg, 10.7 mmol) in one portion. The mixture was stirred at 25 °C for 1Ί h. The solid was formed upon acidification to pH 1 with concentrated HC1 (37%). The precipitate was collected by filtration, washed with water and dried in vacuum to give 639-7 (0.5 g. 49%) as a white solid, which was used for the next step without further purification. +ESIMS: m/z 193.1 [M+H]⁺.

[1230] Compound 639 (28 mg, 45%) was prepared following the general procedure for preparing 606 using 639-7. +ESI-MS: m/z 532.0 [M+H]⁺.

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EXAMPLE 337

Preparation of Compound 643

[1231] To a solution of 643-1 (1.5 g, 6.9 mmol) in DMF (20 mL) was added 2benzyloxyl ethanol (6.3 g, 41 mmol) at 25 °C. The solution was stirred for 6 h and then poured into ILL) (20 mL). The mixture was extracted with EA (2 x 40 mL). The combined organic phase was washed with brine, dried over anhydrous Na^SCfi and concentrated under reduced pressure. The residue was purified by column chromatography using 5-10% EA in PE as the eluent to give a mixture of 643-2 and 643-2A (1.50 g).

[1232] To a solution of 643-2A and 643-2A (1.50 g. crude mixture) in EtOI 1/1I₂O (20/10mL) were added Fe (1.5 g. 26.7 mmol) and NH4CI (1.5 g, 28 mmol) at 25 °C. The solution was heated to 80 °C and stirred for 2 h. The mixture was filtered, and the filtrate was concentrated to give a mixture of 643-3 and 643-3A (1.20 g, crude). The products were used for the next step without further purification.

[1233] A mixture of 643-3 and 643-3A (1.2 g, crude) in H2SO4/H2O (1:1) (lOmL) was cooled to -5 °C. NaNO₂ (376 mg, 5.45 mmol) was added in portions at -5 °C. The solution was stirred at -5 °C for 0.5 h. The solution w'as heated to 120 °C. After stirring 0.5 h at 120 °C, the solution w'as poured into ice water (20 mL) and extracted with

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EA (2 x 20 mL). The organic phase was concentrated at low pressure. The residue was purified by chromatography to give 643-4 (0.3 g, crude).

[1234] To a solution of 643-4 (0.3 g, crude) in DMF (5 mL), K2CO3 (320 mg, 2.3 mmol) was added dropwise CH₃I (2.14 g. 15.1 mmol) at r.t. The solution was stirred for 3 h. The mixture was poured into FLO (10 mL) and extracted with EA (2 x 20 mL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to give crude 643-5 (210 mg), which was used in the next step directly.

[1235] To a mixture of 643-5 (210 mg, crude) in MeOH (2 mL) was added an aq. NaOH solution (2 mL, 2 M) in one portion at 25 °C. The mixture was heated to 60 °C and stirred for 2 h. The mixture was cooled to r.t. and acidified to pl 1=3 4 by the addition of 1 M aqueous HC1. The mixture was extracted with EA (3 x lOmL). The combined organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue w⁷as purified by prep-TLC (EA) to afford 643-6 (110 mg, 56%).

[1236] Compound 643 (wdiite solid, 14 mg. 24%) w⁷as prepared following the general procedure for preparing 606 using 643-6. +ESI-MS: m/z 553.1 [M+H]⁺.

EXAMPLE 338

Preparation of Compound 644

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PCT/US2014/051642 [1237] 644-2 was prepared as provided in PCT Publication No. WO

2013/007663, published January 17, 2013 [1238] 644-4 was prepared following the general procedure for preparing 272 using 644-2.

[1239] A mixture of 644-4 (1.5 g, 5.5 mmol), potassium vinyl tri fluoro borate (1,6g. 11.1 mmol), CS2CO3 (1.8 g, 5.5 mmol) and Pd(dppf)C12 (0.4 g, 0.5 mmol) in i-PrOH (10 mL) was de-gassed. The mixture was heated to 80 °C for 15 h under N2. After cooling to r.t, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography using 5 -2()% DCM in PE to give 644-5 (0.9 g, 74.5%).

[1240] Ozone was bubbled into a solution of 644-5 (0.87 g, 4 mmol) in anhydrous MeOH (10 mL) at -78 °C for 10 mins. After the excess ozone was purged by N2. NaBHi (304 mg, 8 mmol) was added at 25 °C. The solution was stirred at 25 °C for 30 mins. The reaction was quenched with ILO and extracted with EA (3 x 20 mL). The combined organic solutions w^rere washed with brine, dried over anhydrous NasSOq and concentrated under reduced pressure. The residue was purified by column chromatography 10-25% DCM in PE to give 644-6 (0.7 g, 79%) as a solid.

[1241] To a solution of 644-6 (0.5 g, 2.3 mmol) in MeOH (3 mL) was added NaOH (0.5 g, 12.5 mmol) in HiO (3 mL). After stirring at 60 °C for 1 h, the mixture was acidified to pl 1=3-4 by addition of 2 Μ IIC1 solution. The mixture was extracted with EA (3 x 10 mL). The combined organic solutions were washed with brine, dried over NaiSOa and concentrated under reduced pressure to give 644-7 (0.4 g. 85.3%).

[1242] Compound 644 (while solid. 27 mg, 42%) was prepared following the general procedure for preparing 606 using 644-7. +ESI-MS: m/z 548.0 [M+H]⁺.

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EXAMPLE 339

Preparation of Compound 657

[1243] 657-6 was prepared following the general procedure for preparing 606 using 657-1.

[1244] To a stirring solution of 657-6 (2 g, 4.3 mmol) in EtOH (40 mL) were added SnCE ^EEO (3.9 g, 17.3 mmol) and cone. HCl (5.4 mL, 12 M). After stirring at 60 °C for 12 h. the mixture was cooled to r.t., and EtOH was removed under reduced pressure. The residue was diluted with waler (10 mL) and neutralized by sat. aq. Na2CO3 solution. The aqueous phase was extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na₃SO4, filtered and concentrated under reduced pressure.

The residue was purified by column chromatography using 50-100% EA in PE as the eluent to afford 657-7 (0.82 g, 44%) as a yellow⁷ oil. +ESI-MS: m/z 432.3 [M+H]⁺.

[1245] To a solution of 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (1.5 g, 7.2 mmol) in anhydrous DMF (30 mL) were added HATH (2.7 g, 7.2 mmol) and DIEA (2.3 g, 18 mmol). After stirring at 25 °C for 30 mins, a solution of 657-7 (2.5 g, 6.0 mmol) in DMF (5 mL) was added dropwise. The mixture was stirred at 25 °C for 1-2 h. The solution was poured into water (50 mL). and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO₄. filtered and concentrated under

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PCT/US2014/051642 reduced pressure. The residue was purified by column chromatography using DCM:MeOl 1=200:1-80:1 as the eluent to afford 657-8 (2.2 g, 59 %) as yellow oil.

[1246] 657-8 (100 mg, 0.16 mmol), 4-Cl-phenyl boronic acid (50 mg, 0.32 mmol) and Cs₂CO₃ (156 mg. 0.48 mmol) were taken up into a microwave tube in co-solvent dioxane:H2O (1.2 mL, v:v=5:l). The solution was degassed and Pd(dppf)CL (3.5 mg, 0.05 mmol) was added. The sealed tube was heated to 110 °C by microwave irradiation and stirred for 1 h. The solution was cooled to r.t. and poured into water (10 mL). The mixture was extracted with EA (3x5 mL). The combined organic layers were washed with brine, dried over anhydrous Na^SCfi, filtered and concentrated under reduced pressure. The residue was purification by prep-TLC to give 657-9 (49 mg, 44%)

11247] To a solution of 657-9 (49 mg) in CH3CN (1 mL) was added one drop of TMSI at r.t,, and the mixture stirred at r.t. for 10 mins. The mixture was poured into water, neutralized with sat. NaHCO₃ solution, and extracted with EA (3x10 mL). The combined organic layers were washed with brine, dried over anhydrous Na-AOi. filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 657 (15 mg) as a white solid. +ES1-MS: m/z 567.9 [M+H]⁺.

EXAMPLE 340

Preparation of Compound 658

[1248] Compound 658 (white solid, 5 mg) was prepared following the general procedure for preparing 657 using 658-1 and 4-CF₃-phenyl boronic acid. The crude product was purified by prep-HPLC. +F.SI-MS: m/z 602.1 [M+H]⁺.

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EXAMPLE 341

Preparation of Compound 659

[1249] Compound 659 (white solid, 11 mg) was prepared following the general procedure for preparing 657 using 659-1 and 2-methoxy-4-pyridyl boronic acid. The crude product was purified by prep-HPLC. +ESI-MS: m/z 565.1 [M+H]⁺.

EXAMPLE 342

Preparation of Compound 660

[1250] Compound 659 (white solid, 10 mg) was prepared following the general procedure for preparing 657 using 660-1 and 2-methoxy-4-pyridyl boronic acid. The crude product was purified by prep-HPLC. +ESI-MS: m/z 565.1 [M+H]⁺.

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EXAMPLE 343

Preparation of Compound 614

[1251] A mixture of 614-1 (23 mg, 0.1 mmol), 614-2 (50 mg, 0.1 mmol) and TEA (1 mmol) were dissolved in DCM (4 mL). HATU (38 mg, 0.1 mmol) was added, and the mixture was stirred for 30 mins. The mixture was diluted with brine (5mL), and the aqueous phase was extracted with DCM (2 x 5 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO_i and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and hydrogenated over Pd/C (10 mg. 10%) at 15 psi for 17 h. The catalyst was removed by filtration, and the cake was washed with MeOH (5 mL). The combined filtrates was concentrated and purified by prep-HPLC to give 614 (28 mg, 45 %). +ESI-MS: m/z 584.0 [M+H]⁺.

EXAMPLE 344

[1252] Compound 615 (white solid. 43 mg) was prepared following the general procedure for preparing 614 using 615-1 and 615-2. The crude product was purified by prepHPLC. +ES1-MS: m/z 583.1 [M+H]⁺.

EXAMPLE 345

Preparation of Compound 626

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PCT/US2014/051642 [1253] To a solution of 540 (160 mg, 0.26 mmol) in MeOH (2 mL) was added Pd/C (150 mg) under N₂. The suspension was degassed under vacuum and purged with II₂several times. The mixture was stirred at 25 °C for 12 h. The mixture was filtered through a pad ofCelite, and the pad was washed with MeOH. The combined filtrates were concentrated under reduced pressure. The residue was purified by prep-HPLC of acidity w ith HCI to give 626 (69 mg. 43%). +ESI-MS: m/z 570.0 [M+H]⁺.

EXAMPLE 346

Preparation of Compound 627

[1254] A mixture of 627-1 (66 mg, 0.3 mmol). 627-2 (150 mg. 0.3 mmol) and TEA (1 mmol) were dissolved in DCM (4 mL). HATU (120 mg. 0.2 mmol) was added, and the mixture was stirred for 30 mins. The reaction was diluted with brine (5mL), and the aqueous phase w^ras extracted with DCM (2 x 5 mL). The combined organic layer w^ras washed with brine, dried over anhydrous Na₂SC>4 and concentrated under reduced pressure to give crude 627-2. which was used in next step without further purification. +ESI-MS: m/z 764.1 [M+H]⁺.

[1255] To a solution of 627-2 (0.7 g. crude) in MeOH (20 mL) was added L1BH4 (59 mg. 2.8 mmol) in one portion at r.t. Lhe mixture was stirred for 1 h. Lhe reaction was quenched with 2N HCI solution and extracted with EA (3 x 20 mL). The combined organic layer w^ras washed with brine, dried over anhydrous Na₂SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=30:l~3:l as the eluent to afford 627-3 (0.6, 89%) as an oil. +ES1-MS: m/z 736.0 [M+H]⁺.

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PCT/US2014/051642 [1256] Compound 627 (white solid, 180 mg) was prepared following the general procedure for preparing 540 using 627-3. +ESI-MS: m/z 568.1 [M+H]⁺.

EXAMPLE 347

Preparation of Compounds 655 and 656

[1257] Compound 615 (30 mg) was separated by SFC to give solutions of peak 1 and peak 2. The two peaks were acidified by aq. HC1 (2 M) and lyophilized to give 655 (9.2 mg) and 656 (8.9 mg) as a white solid. 655: +ESI-MS: m/z 583.1 [M+H]⁺and 656: +ESIMS: m/z 583.1 [M+II]'/

EXAMPLE 348

Preparation of Compound 622

[1258] 622-1 (white solid, 610 mg) was prepared following the general procedure for preparing 536. +ESI-MS: m/z 760.1 [M+H]⁺.

[1259] Compound 622 (12 mg,) was prepared following the general procedure for preparing 581 using 622-1. LCMS: m/z 592.15 [M+H]⁺.

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EXAMPLE 349

Preparation of Compound 650

650-1 650-2 650-3 650-4 650-5

650-10 650-11 650-12 650-13

650-15 650-16

[1260] 650-17 (white solid, 210 mg) was prepared following the general procedure for preparing 563 using 650-1 and 4-F-phenyl boronic acid. +ES1-MS: m/z 698.1 [M+H]⁺.

[1261] To a stirring mixture of 650-17 (200 mg, 0.28 mmol) in CH₃CN (2 mL) were added Nal (215 mg, 1.4 mmol) and TMSC1 (152 mg, 1.4 mmol). The mixture was stirred at 65 °C for 20 mins. The mixture was cooled to r.t. and diluted with EtOAc. The reaction was quenched with a 10% aqueous solution of Na2S₂O₃. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried

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PCT/US2014/051642 over Na₂SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via prep-IIPLC to afford 650 (10 mg) as a white solid. LCMS 564.20 m/z [M+H]⁺.

EXAMPLE 350

Preparation of Compound 667

[1262] To a solution of 667-1 (100 mg, 0.16 mmol) in THF (1 mL) was added cyclopropvlmagnesium chloride (2 mL, 1 mmol) dropwise at r.t. The mixture was stirred for 2 li. The reaction was quenched with aq. NH4CI and extracted with EA (3x10 mL). The combined organic phase was washed with brine, dried over Na₂SO| and concentrated under reduced pressure. The residue was purified by prep-TLC (PE:EA=1:1) to give 667-2 (62 mg, 58.4%).

[1263] To a solution of 667-2 (62 mg, 0.1 mmol) in DCM (2 111L) was added TFA (2 mL) at r.t. The mixture was stirred for 30 mins. The mixture was neutralized by aq. NallCOa solution and extracted by EA (3x10 mL). The combined organic layers were washed with brine, dried over Na₂SO4 and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 667 (9 mg, 16.3%) as a white solid. +ESI-MS: m/z 554.0 [M+H]⁺.

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EXAMPLE 351

Preparation of Compound 603

603-1 603-2 603-3

603^t o'

[1264] Enantiomer 603-2 (270 mg) was obtained by SFC separation of racemic 603-1 (1.1 g).

[1265] Lo a stirring mixture of 603-2 (270 mg 0.8 mmol) in 2-methylpropan-2-ol (6 mL):H2O (2 mL) at 0 °C were added BocN-OTs (308 mg 1.07 mmol) and KbOsOwELO (60 mg, 0.16 mmol) at r.t. Lhe mixture was stirred at r.t. for 30 h. The mixture -was diluted with water and extracted with DCM (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA=1:1 as the eluent to afford 603-3 (-200 mg,-60%). +ESI-MS: m/z 638.1 [M+H]⁺.

[1266] To a mixture of 603-3 (200 mg, 0.32 mmol) in DCM (6 mL) was added TFA (3 mL) at r.t. The mixture was stirred for 30 mins, neutralized with aqueous NaHCO₃and extracted with EA (3 x 10 mL). The combined organic layers were washed by brine, dried over Na₂SO₄ and concentrated under reduced pressure to give crude 603-4 (110 mg), which was used without further purification. +ES1-MS: m/z 538.1 [M+H]⁺.

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PCT/US2014/051642 [1267] To a solution of 4-(cyclopropoxy)-3-methoxy-benzoic acid (37 mg, 0.17 mmol), IIATLJ (100 mg 0.26 mmol) and DIPEA (57 mg, 0.44 mmol) in anhydrous DMF (3 mL) was added 603-4 (110 mg crude) at r.t. The solution was stirred for 5 h at r.t. with TLC monitoring. The mixture was diluted with 1.0 N aqueous NaHCO₃ solution and extracted with EA (3 x 10 mL). The combined organic layers were washed by brine, dried over anhydrous Na₂SO4. and concentrated under reduced pressure. The residue was purified by column chromatography using PE:EA = 1:1 as the eluent and prep-HPLC to give 603-5 (43 mg, 28.7%). +ESI-MS: m/z 728.1 [M+Hf.

[1268] To a stirring mixture of 603-5 (15 mg, 0.041 mmol) in CH₃CN (1 mL) at r.t. were added Nal (32 mg. 0.2 mmol) and TMSC1 (22 mg, 0.2 mmol). The mixture was stirred at 55 °C for 15 mins. The mixture was diluted with EtOAc and washed with a 10% aq. Na₂S₂O₃ solution. The organic layer was washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The reaction was concentrated and the crude product was purified by prep-HPLC to provide 603. +ESI-MS: m/z 594.20 [M+H]⁺.

EXAMPLE 352

Preparation of Compound 575 ci [1269] Cyclobutanone (17 pL, 0.22 mmol) and sodium cyanoborohydride (47 mg, 0.22 mmol) were added to a solution of 314 (43 mg. 0.074 mmol) every 30 mins for 6 h. The mixture was diluted with EtOAc, washed with IN HCI and brine, dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC to give 575 (14 mg. 23%). LCMS: m/z 637.20 [M+H]⁺.

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EXAMPLE 353

Preparation of Compound 577

[1270] Compound 577 was prepared following the general procedure for preparing 575. LCMS: m/z 639.10 [M+H]⁺.

EXAMPLE 354

Preparation of Compound 581

H [1271] 577 (12 mg. 0.019 mmol) was hydrogenated over 10% Pd/C (3 mg) in

EtOH (2 mL) for 1 h. The catalyst was removed by filtration and the crude product was purified by reverse-phase 11PLC to give 581 (8 mg, 66%). LCMS: m/z 604.20 [M+H]⁺.

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EXAMPLE 355

Preparation of Compound 576

H [1272] Pd(dppf)Cl₂ (66 mg. 0.091 mmol) was added to a solution of 2,4-dichloro4-iodopyridine (0.50 g. 1.8 mmol). (l-(tert-Butoxycarbonyl)-1.2,3.6-tetrahydropyridin-4yl)boronic acid (0.54 g. 1.8 mmol) and cesium carbonate (1.8 g. 5.5 mmol) in dimethoxyethane (10 mL) and water (1 mL). The mixture was heated under microwave irradiation at 110 °C for I h. The mixture was diluted with EA, washed with brine, dried over anhydrous Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-1 (0.47 g, 72%). LCMS: m/z 329.00 [M+Hf.

[1273] A solution of 576-1 (0.83 g. 2.5 mmol) and platinum oxide (83 mg) in EtOH was stirred under H₂ atmosphere for 1 h. The mixture was filtered to remove catalyst and concentrated. The product (0.80 g, 96%) was used without further purification. LCMS: m/z 331.05 [M+H]⁺.

[1274] HC1 (4N in dioxane. 3 mL) was added to 576-2 (0.80 g, 2.4 mmol). The mixture was stirred at r.t. for 30 mins and concentrated under reduced pressure. The crude product was dissolved in ClI₂C1₂ (10 mL), and DIEA (1.1 mL. 6.0 mmol) and benzyl chloroformatc (0.41 mL, 2.9 mmol) were added. The reaction was stirred at r.t. for 1 h. The

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PCT/US2014/051642 mixture was diluted with EA, washed with IN HC1 and brine, dried over anhydrous Na₂SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-3 (0.49 g, 54%). LCMS: m/z 365.05 [M+H]⁺.

[1275] Pd(dppf)Cl₂ (0.45 g. 0.61 mmol) was added to a solution of 576-3 (0.49 g. 1.3 mmol), 1-(trifluoromethyl)vinylboronic acid hexylene glycol ester (0.30 g, 1.3 mmol). CS2CO3 (1.3 g, 4.0 mmol) in DME (3 mL) and water (0.3 mL). The reaction vessel was heated under microwave irradiation for 20 mins at 110 °C. The mixture was diluted with EA. The organic phase was washed with water and brine, dried over anhydrous Na₂SO4 and concentrated. The residue was purified by chromatography on silica gel (EAthexane) to give 576-4 (0.23 g. 41%). LCMS: 111/z 425.05 [M+H]⁺.

[1276] Pd(dppf)Cl₂ (20 mg, 0.027 mmol) was added to a solution of 576-4 (0.23 g, 0.54 mmol). 3-chloro-4-fluorophenyl boronic acid (95 mg. 0.54 mmol). CS2CO3 (0.53 g, 1.6 mmol) in DME (2 mL) and water (0.2 mL). The reaction vessel was heated under microwave irradiation at 110 °C for 1 h. The mixture w'as diluted with EA. The organic phase was washed with water and brine, dried over anhydrous NaoSCfi and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-4 (0.11 g, 38%). LCMS: m/z 519.10 [M+H]⁺.

[1277] Potassium osmate (11 mg, 0.029 mmol) was added to a solution of 576-5 (0.11 g, 0.21 mmol) and tert-butyl (tosyloxy)carbamatc (91 mg, 0.33 mmol) in t-butanol (1 mL) and water (0.33 mL). The solution was stirred overnight at r.t. The crude mixture was purified by chromatography on silica gel (EA:hexane) to give 576-6 (0.12 g. 85%). LCMS: m/z 652.20 [M+H]⁺.

[1278] HC1 (2 mL, 4N in dioxane) was added to 576-6 (0.12 g, 0.18 mmol), and the mixture was stirred at r.t. for 2 h. The solvent was removed by evaporation and the amine salt was re-dissolved in DMF (1 mL). 4-cyclopropoxy-3-methoxybenzoic acid (57 mg, 0.28 mmol), HATU (0.14 g. 0.37 mmol) and DIEA (0.14 mL. 0.74 mmol) were added, and the mixture w'as stirred at r.t. for 2 h. The mixture was diluted with EA. The organic phase was washed with IN HC1, water and brine, dried over anhydrous Na₂SC>4 and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 576-7 (35 mg, 26%). LCMS: m/z 742.20 [M+H]⁺.

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PCT/US2014/051642 [1279] Chlorotrimethylsilane (23 μΙ.. 0.24 mmol) was added dropwise to a solution of 576-7 (35 mg, 0.047 mmol) and Nal (28 mg, 0.24 mmol) in CH₃CN (1 mL). and the mixture was stirred for 30 mins. The mixture was diluted with EA, washed with Na₂S₂O3 and brine, dried and concentrated. The crude product was purified by reverse-phase HPLC to provide 576 (13 mg. 37%). LCMS: m/z 609.15 [M+H]⁺.

EXAMPLE 356

Preparation of Compound 579

[1280] Ethyl acetimidate hydrochloride (150 mg, 1.2 mmol) was added to a solution of 314 (50 mg, 0.086 mmol) in EtOH (3 mL). The mixture heated at reflux for 24 h. The mixture was diluted with EA, washed with brine, dried and concentrated. The crude product w'as purified by reverse phase HPLC to give 579 (8 mg. 16%). LCMS: m/z 624.15 [M+H]⁺.

EXAMPLE 357

Preparation of Compound 585

[1281] Compound 585 was prepared following the general procedure for preparing 579 using 318 and ethyl acetimidate. LCMS: m/z 590.20 [M+H]⁺.

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EXAMPLE 358

Preparation of Compound 580

[1282] Benzyl(2-2(3-amino-l ,1,1 -trifluoro-2-hydroxypropan-2-yl)-6-(3-chloro-4fluorophenyl)pyridine-4-yl)propan-2-yl)carbamate was coupled with 4-(2-amino-2 oxoethoxy)-3-methoxybenzoic acid following the general procedure for 576-7. 580-1 was hydrogenated following the general procedure for preparing 581. LCMS: m/z 565.15 [M+H]⁺.

EXAMPLE 359

Preparation of Compound 586

[1283] 586-1 was prepared following the general procedure for 576-7. HC1 in dioxane (3 mL) was added to 568-1 (92 mg, 0.18 mmol), and the mixture was stirred at r.t. for 3 h. The mixture was concentrated, and the crude product purified by reverse-phase HPLC to provide 586 (43 mg, 47%). LCMS: m/z 566.20 [M+H] .

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EXAMPLE 360

Preparation of Compound 592

[1284] Compound 592 was prepared following the general procedure for 586 using 4-acetamido-3-methoxybenzoic acid. LCMS: m/z 583.15 [M+H]⁺.

EXAMPLE 361

Preparation of Compound 593

[1285] Compound 593 was prepared following the general procedure for 586. LCMS: m/z 619.00 [M+H]⁺.

EXAMPLE 362

Preparation of Compound 596

[1286] Compound 596 was prepared following the general procedure for 586 using 4-(3-hydroxycyclobutoxy)-3-methoxybenzoic add. LCMS: m/z 578.20 [M+H]⁺.

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EXAMPLE 363

Preparation of Compound 616

[1287] To a stirring mixture of methyl 4-hydroxy-3-methoxybenzoate (1 g, 5.49 mmol) in DMF (5 mL) at r.t. were added K2CO3 (1.14 g, 8.24 mmol) and 2bromoacetonitrile. The mixture was stirred at r.t. for several hours and then diluted with EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4. filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel chromatography to afford 616-1 as a white solid.

[1288] To a stirring mixture of 616-1 (190 mg. 0.856 mmol) in DMF (2 mF) were added NaNj (71.5 mg, 1.1 mmol) and NH4CI (59 mg, 1.1 mmol). The mixture was carried out under microwave irradiation for 45 mins at 100 °C. The mixture was diluted with EtOAc and water, and the layers were separated. To the aqueous layer was added a 10% aqueous HCI solution until a white precipitation was formed. The tetrazole-product was filtered off. and then dissolved directly in aq. NaOH solution (1.5 ml., 2N). The mixture was heated at 80 °C for 30 mins. The mixture was cooled to r.t. and acidified with a 10% aq. HCI solution. The white solid was filtered off and dry under reduced pressure. Crude 616-2 was used without further purification. LCMS: m/z 265.05 [M+H]⁺.

[1289] Compound 616 was prepared following the general procedure for 586 using 616-2. TCMS: m/z 624.15 [M+H]⁺.

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EXAMPLE 364

Preparation of Compound 599

[1290] 599-1 was prepared following the general procedure for 576-7.

Pd(dppf)C12 (12 mg, 0.016 mmol) was added to a solution of 599-1 (0.23 g, 0.32 mmol), pyridine-4-boronic acid (65 mg. 0.016 mmol) and cesium carbonate (0.31 g, 0.96 mmol) in dimethoxyethane (2 mL) and water (0.2 mL). The mixture was heated under microwave irradiation at 110 °C for 20 mins. The mixture was diluted with EA. washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 599-2 (0.11 g, 50%).

[1291] 599-2 was prepared following the general procedure for 586 to give 599.

LCMS: m/z 569.20 [M+II]'.

EXAMPLE 365

Preparation of Compound 601

[1292] DIEA (87 pL, 0.50 mmol) was added to a solution of 317 (0.10 g, 0.16 mmol), acetic acid (20 mL, 0.33 mmol) and HATU (0.14 g, 0.35 mmol) in DMF. The mixture was stirred at r.t. for 1 h. The crude product was purified by reverse phase HPLC to provide 601 (17 mg, 17%). LCMS: m/z 642.15 [M+H]⁺.

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EXAMPLE 366

Preparation of Compound 611

O'

H [1293] Compound 611 was prepared following the general procedure for 601 using 320. LCMS: m/z 594.20 [M+H]⁺.

EXAMPLE 367

Preparation of Compound 612

[1294] Compound 612 was prepared following the general procedure for 601 using 322. LCMS: m/z 641.15 [M+H]⁺.

EXAMPLE 368

Preparation of Compound 621

[1295] Compound 621 was prepared following the general procedure for 601 using 580. LCMS: m/z 607.20 [M+H]⁺.

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EXAMPLE 369

Preparation of Compound 620

[1296] Compound 620 was prepared following the general procedure for 601 using

586. LCMS: m/z 608.2 [M+H]⁺.

EXAMPLE 370

Preparation of Compound 595

[1297] Isopropylmagnesium chloride (2M in THF, 2.0 mL. 4.0 mmol) was added dropwise to a solution of 2,6-dichloro-4-iodopyridine (1.0 g. 3.7 mmol) at -40 °C. The solution was stirred for 30 mins. 3-Oxetanone (0.28 mL. 4.4 mmol) was added dropwise. The mixture was stirred and warmed to r.t. for 2 h. The reaction was quenched with IN HCL extracted with FA, washed with brine, dried and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 595-1 (0.42 g, 51%).

[1298] Methanesulfonylchloride (1.1 mL. 15 mmol) was added dropwise to a solution of 595-1 (2.14 g, 9.7 mmol) and diisopropylethylamine (3.4 mL, 19 mmol) in CH₂C1₂. The mixture was stirred at 0 °C for 1 h. The mixture was washed with IN HC1 and

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PCT/US2014/051642 brine, dried and concentrated. The residue was purified by chromatography on silica gel (EA:hexane) to give 595-2 (1.91 g, 66%).

[1299] Sodium azide (0.83 g. 1.3 mmol) was added to a soltuion of 595-2 (1.91 g, 0.64 mol) in DMSO (3 mL), and the mixture was stirred at 70 °C for 2 h. The mixture was diluted with EA, washed with water and brine, dried and concentrated. The product was purified by chromatography on silica gel (hexane:EA) to provide 595-3 (0. 67 g, 42%).

[1300] Trimethylphosphine (IM in THF, 2.2 mL, 2.2 mmol) was added to a solution of 595-3 (0.357 g, 1.5 mmol) in EA (5 mL). The mixture was stirred for 20 mins. Water (0.5 mL) was added, and the mixture was stirred at 70 °C for 1 h. The mixture was washed with brine, dried and concentrated to provide 595-4 (0.31 g, 93%) which was used without further purification.

[1301] Benzyl chloroformate (0.98 mL. 6.9 mmol) was added to a solution of 5954 (4.6 mmol) in THF (15 mL) and sat. sodium carbonate (15 mL). The mixture was stirred at r.t. overnight, and the aqueous layers were separated. The organic layer was washed with brine, dried and concentrated. The product was purified by chromatography on silica gel (hexane:EA) to provide 595-5 (1.4 g, 87%).

[1302] Compound 595-6 was prepared following the general procedure for 576-4. LCMS: m/z 413.05 [M+H]⁺. Compound 595-7 was prepared following the general procedure for 576-5. LCMS: m/z 473.10 [M+H]⁺. Compound 595-8 was prepared following the general procedure for 576-6. LCMS: m/z 606.15 [M+H]⁺.

[1303] 595-8 (75 mg, 0.12 mmol) was dissolved in hexafluoroisopropanol (1.5 mL). The solution was heated under microwave irradiation at 150 °C for 65 mins. The mixture was concentrated, and crude 595-9 was used without further purification. LCMS: m/z 505.46 [M+H]⁺.

[1304] 595-10 was prepared following the general procedure for 576-7. LCMS:

m/z 696.20 [M+H]⁺. Compound 595 was prepared following the general procedure for 580 using 595-10. LCMS: m/z 562.15 [M+H]⁺.

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EXAMPLE 371

Preparation of Compound 602

[1305] Benzyl chloroformate (0.61 mL, 4.3 mmol) was added dropwise to a solution of 602-1 (0.86 g. 2.9 mmol) and diisopropylethylamine (1.0 mL, 5.7 mmol) in

CH2CI2 (10 mL). The mixture was stirred at r.t. overnight. The mixture was washed with IN

HC1 and brine, dried and concentrated. Crude 602-2 (0.73 g. 58%) was purified by chromatography (hexane:EA). LCMS: m/z 433.05 | MI 11.

[1306] 602-3 was prepared following the general procedure for 576-4. LCMS:

m/z 439.10 [M+H]⁺. 602-4 was prepared following the general procedure for 576-6. LCMS: m/z 572.15[M+H]⁺. 602-5 was prepared following the general procedure for 576-7. LCMS: m/z 679.20 [M+H]⁺. Compound 602 was prepared following the general procedure for 580 using 602-5. LCMS: m/z 511.15 [M+H]⁺.

EXAMPLE 372

Preparation of Compound 578

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PCT/US2014/051642 [1307] Trifluoroacetic acid (0.3 mL) was added to 578-1 (55 mg, 0.069 mmol) in

CI I2CI2, and the mixture was stirred at r.t. for 4 mins. The reaction was quenched with cold sodium bicarbonate and extracted with CH2CI2. The combined organic extracts were washed with brine, dried, concentrated and used without further purification.

[1308] Potassium carbonate (50 mg, 0.35 mmol) was added to a solution of 578-2 (0.069 mmol) and tert-butyl bromoacetate (30 pL. 0.21 mmol) in DMF (1 mL). The mixture was heated at 55 °C for 1 h. The mixture was diluted with EA, and washed with water and brine. The crude product was purified by column chromatography (hexane:EA) to provide 578-3. LCMS: m/z 790.20 [M+H]⁺.

[1309] Compound 578 was prepared following the general procedure for 576 using 578-3. LCMS: m/z 600.15 [M+H]⁺.

EXAMPLE 373

Preparation of Compound 619

F

[1310] 619-1 w^ras prepared following the general procedure for 576. Compound

619 was prepared following the general procedure for 580. LCMS: m/z 525.15 [M+H]⁺.

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EXAMPLE 374

Preparation of Compound 635

nh₂ [1311] DIEA (90 pL, 0.52 mmol) was added to a solution of 635-1 (72 mg, 0.17 mmol), 8-methoxyquinoline-6-carboxylic acid (45 mg, 0.21 mmol) and HATU (98 mg, 0.26 mmol). The mixture was stirred at r.t. for 2 h. The mixture was purified by reverse-phase HPLC to provide 635-2 (50 mg. 48%). LCMS: m/z 601.10 [M+H]⁺.

[1312] Pd(dppf)Cl₂ (3 mg, 0.0041 mmol) was added to a solution of 635-2 (50 mg, 0.083 mmol), 4-fluorophenyl boronic acid (17 mg, 0.12 mmol), K3PO4 (0.11 mg, 0.22 mmol), KH₂PC>4 (45 mg. 0.22 mmol) in DME (1 mL), EtOH (0.6 mL) and water (0.2 mL). The solution was heated under microwave irradiation at 110 °C for 4 h. The mixture w^ras diluted with EA, washed with brine, dried and concentrated. Crude 635-3 was purified by silica gel chromatography (MeOH:EtOAc). LCMS: m/z 661.20 [M+H]⁺.

[1313] 635-3 (27 mg) w^ras dissolved in MeOH (1 mL). To this stirring mixture was added a solution of HC1 in dioxane (0.2 mL). The mixture was stirred at r.t. for 5 mins. The mixture was concentrated, and 635 (5 mg, 25%) was purified by reverse-phase HPLC. LCMS: m/z 557.15 [M+H]⁺.

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EXAMPLE 375

Preparation of Compound 637

[1314] Chloromethanesulfonyl chloride (0.4 mL, 4.4 mmol) was added dropwise to a solution of ammonia (0.5 M in dioxane, 8.8 mL, 4.4 mmol) and DIEA (0.92 mL, 5.3 mmol) at 0 ⁽’C. The solution was stirred for 1 h. The reaction was washed with IN IIC1 and brine, dried and concentrated. The crude product was used without further purification.

[1315] Potassium carbonate (1.2 g. 8.8 mmol) was added to a solution of methyl vanillate (0.40 g, 2.2 mmol) and 637-1 (4.4 mmol) in DMF (2.0 mL). The mixture was stirred at 65 °C overnight. The reaction was diluted with EA. washed with water and brine, dried and concentrated. The crude product was purified by silica gel chromatography (hexane:EA) to provide 637-2 (50 mg, 8%).

[1316] NaOH (2N, 1 mL) w^ras added to a solution of 637-2 (50 mg, 0.18 mmol) in MeOH (3 ml,). The mixture was stirred at r.t. overnight. The mixture was acidified by the addition of 2N HC1 and extracted with EA. The organic extracts were washed with brine, dried and concentrated. Crude 637-3 was used without further purification.

[1317] 637-4 was prepared following the general procedure for 576-7.

Compound 637 was prepared following the general procedure for 586. LCMS: m/z 635.15 [M+H]⁺.

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EXAMPLE 376

Preparation of Compound 618

[1318] Cesium carbonate (1.0 g, 5.9 mmol) as added to vanillic acid (2.0 g. 12 mmol) suspended in 90% aq. MeOH (20 mL). The mixture was stirred at r.t. for 30 mins. The solvents were removed and the crude product was dried by co-evaporating (2x) with toluene. The cesium salt was re-dissolved in DMF (15 mL). Benzyl bromide was added, and the mixture was stirred at r.t. overnight. The mixture was diluted with EA. washed with water and brine, dried and concentrated. The product was purified by silica gel chromatography (hexane:EA) to yield 618-1 (0.4 g, 12%).

[1319] Ethyl bromoacetate (0.34 mL, 3.1 mmol) was added to a solution of 618-1 (0.4 g, 1.5 mmol) and potassium carbonate (0.64 g. 4.6 mmol) in DMF (3 mL). The mixture was stirred at r.t. for 3 h. The mixture was washed with water and brine, dried and concentrated. The crude product was purified by column chromatography (hexane:EA) to yield 618-2 (0.177 g, 34%).

[1320] 618-2 (0.177 g 0.51 mmol) was hydrogenated over 10% Pd/C (35 mg) in

EtOH for 45 mins. The catalyst was removed by filtration, and the mixture was concentrated to yield 618-3 (0.13 g. 100%). which was used without further purification.

[1321] 618-4 was prepared following the general procedure for 576-7. LCMS:

m/z 728.20 [M+H]⁺. NaOH (2N, 2 mL) was added to a solution of 618-4 (0.302 g, 0.43

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PCT/US2014/051642 mmol) in MeOH (10 mL). The mixture was stirred overnight at r.t. The mixture was acidified with IN HO and extracted with EA. The organic extracts were washed with brine, dried and concentrated to yield 618-5 (0.29 g, 92%). LCMS: m/z 700.20 [M+H]⁺.

[1322] DMAP was added to a solution of 618-5 (50 mg, 0.071 mmol), methyl sulfonamide (10 mg. 0.11 mmol) and EDCI (16 mg, 0.086 mmol) in DMF (1 mL). The mixture was stirred at r.t. overnight. The product was purified by reverse-phase HPLC to yield 618-6 (27 mg). LCMS: m/z 777.05 [M+H]⁺. Compound 618 was prepared following the general procedure for 586. LCMS: m/z 677.05 [M+H]⁺.

EXAMPLE 377

[1323] Compound 617 was prepared following the general procedure LCMS: m/z 628.15 [M+H]⁺.

for

586.

EXAMPLE 378

Preparation of Compound 641

641-8

NHCBz

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PCT/US2014/051642 [1324] To a stirring mixture of 641-1 (950 mg, 1.9 mmol) in t-BuOH:water (3:1, 3 mL total volume) at r.t. were added potassium osmate dihydrate (105 mg, 0.3 mmol) and tert-butyl tosyloxycarbamate (1 g, 3.8 mmol). The mixture was stirred at r.t. overnight. The mixture was diluted with water and DCM. The aqueous layer was extracted with DCM. dried over Na₂SC>4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 641-3 as a minor product (200 mg, 10%); LCMS: m/z 527.2 [M+H]⁺.

[1325] tert-butyl tosyloxycarbamate was prepared as follows. To a stirring mixture of tert-butyl hydroxycarbamate (2 g, 15 mmol) in THF (10 mL) at 0 °C was added TsCl (2.8 g, 15 mmol) and TEA (2.2 mL, 15.8 mmol). The mixture was stirred at 0 °C for 20 mins and then quickly warmed to r.t. for 5 mins. The mixture was diluted with DCM and washed with water. An aqueous workup with DCM gave the crude product, which was purified via a silica gel to afford tert-butyl tosyloxycarbamate as a white solid.

[1326] To a stirring mixture of 641-3 (200 mg. 0.39 mmol) in CH₂C1₂ (2 mL) at r.t. were added TsCl (376 mg, 1.96 mmol) and TEA (320 pL, 2.34 mmol). The mixture was stirred at r.t. for 30 mins. The reaction was quenched with sat. NaHCO₃ solution. The layers were separated. The aqueous layer was extracted with EtOAc (2 x 25 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. Chromatography of the crude product afforded 641-4 (128 mg) as a colorless oil. LCMS: m/z 681.10 [M+H]⁺.

[1327] To a stirring mixture of 641-4 (128 mg, 0.188 mmol) in acetone (2 mL) at r.t. was added LiBr. The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure. Chromatography of residue afforded 6415 as a colorless oil (80 mg. 72% yield). LCMS: m/z 589 [M+H]⁺.

[1328] To a stirring mixture of 641-5 (80 mg. 0.135 mmol) in DCM (1.5 mL) at 0 °C was added DAST (58 pL, 0.41 mmol). The mixture was stirred at 0 °C for 30 mins and then quickly warmed to r.t. for 5 mins. The reaction was quenched with a cold aq. NaHCO₃solution. The aqueous layer was extracted with DCM. dried over Na₂SO4. filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 641-6 (56 mg. 74% yield). LCMS: m/z 591.0 [M+H]⁺.

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PCT/US2014/051642 [1329] To a stirring mixture of 641-6 (50 mg, 0.084 mmol) in DMF (1 mL) were added tetrabutylammonium azide (240 mg, 0.84 mmol) and tetrabutylammonium iodide (12 mg). The mixture was stirred at 100 °C for several hours. The mixture was directly loaded onto a silica gel column, eluting with hexane:EtOAc to afford 641-7 (30 mg, 64%) as a colorless oil. LCMS: m/z 554.10 [M+H]⁺.

[1330] To a stirring mixture of 641-7 (30 mg. 0.054 mmol) in THF:water (10:1. 1.1 mL) was added triphenylphosphine, polvmer-bound (142 mg. 0.54 mmol). The mixture was stirred at 70 °C for 30 mins and then cooled to r.t. The mixture was filtered through a plug of celite. The plug was washed several times with EtOAc. The crude mixture was concentrated under reduced pressure, and the crude product was used in the next step without further purification.

[1331] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid in DMF (1 mL) were added HATU (21 mg. 0.054 mmol) and DIPEA (15 pL. 0.11 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 641-8 in DMF (0.5 mL) was added. The mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO₃ (10 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford 641-9 (20 mg, 52%, 2 steps) as a white solid. LCMS: m/z 718.2 [M+H]⁺.

[1332] To a stirring mixture of 641-9 (20 mg, 0.0286 mmol) in AcCN (1 mL) at r.t. were added Nal (22 mg. 0.143 mmol) and TMSC1 (19 mg. 0.143 mmol). The mixture was warmed to 60 C until the starting materials were consumed. The mixture was cooled to r.t. and diluted with CH₂C1₂. The mixture was washed with a 10% aq. solution of Na₂S₂O3. The aqueous layer was extracted with DCM (2 x 10 mL). dried over Na₂SO4. filtered and concentrated under reduced pressure. The crude product was further purified via prep-HPLC to afford 641. LCMS: m/z 584.15 [M+H]⁺.

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EXAMPLE 379

Preparation of Compound 573

[1333] To a stirring solution of 573-1 (30 mg, 0.41 mmol) in EtOAc.EtOII (5 mL:5mL) was added Pd/C (20 mg). The mixture was placed under a 1¾ balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure, which was used without further purification.

[1334] The N-Boc protected amine was dissolved in a 4N HC1 in dioxane. The mixture was stirred overnight at r.t. The crude product mixture was concentrated under reduced pressure. The crude product mixture was purified via a prep-HPTC to afford 573 as a white solid. LCMS: m/z 590.15 [M+H]⁺.

EXAMPLE 380

Preparation of Compound 598

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PCT/US2014/051642 [1335] To a stirring mixture of 2,6-dichloroisonicotinonitrile (1 g, 5.78 mmol) in Et₂0 at r.t. under Ar was added Ti(OiPr)₄ (1.97 mL, 6.65 mmol). The mixture was stirred for 10 mins and then cooled to 0 °C. A solution of EtMgBr (3.54 mL, 12.14 mmol) in 2methyltetrafuran was added over 10 mins. The mixture was stirred at r.t. for 1 h. and then cooled to 0 °C. BF₃.OEt (1.3 mL. 10.58 mmol) was added. The mixture was warmed to r.t. and stir for 30 mins. The reaction was quenched with IN HCI (5 mL) and then 2N NaOH (10 mL). The mixture was diluted with DCM. The aqueous layer was extracted with DCM, dried over MgSO4. filtered and concentrated under reduced pressure. Chromatography of the residue afford 598-1 (100 mg, 8.5%) as a colorless oil. LCMS: m/z 203.1 [M+H]⁺.

[1336] To a stirring mixture of 598-1 (100 mg, 0.49 mmol) in DCM (1 mL) at 0 C were added CBzCl (84.2 mg. 0.49 mmol) and DIPEA (86 pL, 0.49 mmol). The mixture was warmed to r.t. for 20 mins. The reaction was quenched with a cold sat. NaHCO₃solution. The aqueous layer was extracted with DCM, dried over Na₂SO₄. filltered and concentrated under reduced pressure. Chromatography of the residue afford N-CBz protected amine (100 mg, 60%). LCMS: m/z 337.0 [M+H]⁺.

[1337] To a stirring mixture of benzyl (1-(2,6-dichl oropyridin-4yl)cyclopropyl)carbamate (100 mg. 0.297 mmol) in DME (2 mL. deoxygenated prior to using) were added 4,4.6-trimethyl-2-(3,3.3-trifluoroprop-l-en-2-yl)-L3,2-dioxaborinane (132 mg, 0.59 mmol), a solution of Cs₂CO₃ (290 mg, 0.89 mmol in 0.3 mL of water) and PdCb(dppf) (45 mg, 0.062 mmol). The mixture was heated under microwave irradiation for 1 h at 110 °C. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product was purified via a silica gel chromatography to afford desired product. The mixtures was used in the next step without further purification (70 mg). LCMS: m/z 397.10 [M+H]⁺.

[1338] To a stirring mixture of products from the previous step (70 mg. 0.176 mmol) in DME (1.5 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (36 mg, 0.259 mmol), a solution of Cs₂CO₃ (171 mg, 0.52 mmol in 0.3 mL of water), and PdCl₂(dppf) (26 mg, 0.035 mmol). The mixture was carried out under microwave irradiation at 110 °C for 1 h. The crude product was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc, dried over MgSO₄. filtered and concentrated under

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PCT/US2014/051642 reduced pressure. The crude product was purified via a silica gel chromatography to yield benzyl (l-(2-(4-fluorophcnyl)-6-(3,3,3-trifluoroprop-l-en-2-yl)pyridin-4yl)cyclopropyl)carbamate as the desired product. LCMS: m/z 457. [M+H]⁺.

[1339] To a stirring mixture of 598-2 (50 mg, 0.085 mmol) in t-BuOH:water (3:1. 1.3 mL) at r.t. were added potassium osmate dihydrate (8 mg, 0.0215 mmol) and tertbutyl tosyloxycarbamate (62 mg, 0.215 mmol). The mixture was stirred at r.t. overnight, and then diluted with water and DCM. The aqueous layer was extracted with DCM. dried over MgSCfi, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 598-3 (24 mg. 37%). LCMS: m/z 590.20 [M+H]⁺.

[1340] The N-Boc protected amine was dissolved in a solution of HC1 in dioxane (2 mL, 4N) at r.t. The mixture was stirred at r.t. until the starting material was consumed. The mixture was concentrated under reduced pressure to afford the crude amino alcohol, which was used without further purification. LCMS: m/z 490.10 [M+H]⁺.

[1341] To a stirring mixture of (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid (9 mg, 0.04 mmol) in DMF (0.5 mL) were added HATU (15.2 mg, 0.04 mmol) and DIPEA (17 llL. 0.1 mmol). The mixture was stirred at r.t. for 10 mins. A solution of the crude amino alcohol in DMF (0.2 mL) was added. The mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. NaHCCfi solution (1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prcp-HPLC to afford benzyl (l-(2-(4-fluorophcnyl)-6-( 1,1.1-trifluoro-2-hydroxy3-(4-((R)-2-hydroxypropoxy)-3-methoxybenzamido)propan-2-yl)pyridin-4yl)cyclopropyl)carbamate (7 mg, 24% 2 steps) as a white solid. LCMS: m/z 698.2 [M+H]⁺.

[1342] To a stirring mixture of 598-4 (7 mg, 0.01 mmol) in AcCN (0.5 mL) at r.t. were added Nal (7.5 mg, 0.05 mmol) and TMSC1 (5.4 mg, 0.05 mmol). The mixture was warmed to 60 °C until the starting material was consumed. The mixture was cooled to r.t. and diluted with CFLCfi. The mixture was washed with a 10% aq. Na₂S₂O3 solution. The aqueous layer w^ras extracted with DCM (2 x 10 mL), dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was further purified via prep-HPLC to afford 598. LCMS: m/z 564.20 [M+H]⁺.

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EXAMPLE 381

Preparation of Compound 600

[1343] To a stirring solution of 533 (10 mg, 0.016 mmol) in EtOAc.'EtOH (5 mL:l mL) was added Pd/C (15 mg). The mixture was placed under a IE balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed several times with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure and purified via prep-HPLC to afford 600 as a w'hite solid (3 mg, 32%). LCMS: m/z 564.2 [M+H]⁺.

EXAMPLE 382

Preparation of Compound 594

[1344] Iodomethane (0.66 mL, 11 mmol) was added dropwise to a solution of 2chloro-3-hydroxy-6-(hydroxymethyl)-4-iodopyridine (2.03 g, 7.1 mmol) and potassium

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PCT/US2014/051642 carbonate (2.0 g, 14 mmol) in DMF (8 mL). The mixture was stirred at r.t. for 1 h. The mixture was diluted with EA, washed with water and brine, dried and concentrated. The product (1.77 g. 64%) crystallized upon standing.

[1345] DIPEA (2.0 mL. 12 mmol) w'as added dropwise to a solution of (6-chloro4-iodo-5-methoxypyridin-2-yl)methanol (1.77 g. 5.91 mmol), tert-butylchlorodimethylsilane (1.3 g, 8.9 mmol) and a catalytic amount of imidazole in CH₂C1₂ (10 mL). The mixture was stirred at r.t. overnight. The mixture was diluted with CH₂C1₂, washed with IN HC1 and brine, dried and concentrated. The crude product was purified by column chromatography (hexane:EA) to yield the product (2.18 g. 75%) as a white solid.

[1346] Copper cyanide (1.0 g, 12 mmol) was added to a solution of 6-(((tertbutyldimethylsilyl)oxy)methyl)-2-chloro-4-iodo-3-methoxypyridine (1.0 g, 2.4 mmol) in dimethyl acetamide (3 mL). The mixture w^ras heated at 140 °C for 2 h, and then diluted with DCM. A 10% aq. solution of NH4OH was added. The mixture was stirred at r.t. for 20 mins, and the layers were separated. An aqueous work up with EtOAc was followed. Chromatography of residue afforded 6-(((tert-biityldimethylsilyl)oxy)methyl)-2-chloro-3methoxyisonicotinonitrile (520 mg,70%) as a colorless oil.

[1347] To a stilling mixture of 6-(((tert-butyldimethylsilyl)oxy)methyl)-2-chloro3-mcthoxyisonicotinonitrile (520 mg, 1.66 mmol) in Et₂O (3.9 mL) at 0 °C was added a solution of MeMgBr in 2-methyltetrafuran (1.47 mL, 4.71 mmol). After 1 h of stirring at r.t.. Ti(OiPr)4 was added. The mixture was heated at reflux for 2 h and then diluted with CELCL. The mixture was cooled to r.t., and copious quantities of Celite were added. The crude mixture was basified with a solution of NaOH (2 mL. 2N) and filtered through a plug of Celite. The plug w'as washed several times with DCM. The filtrate was washed with a 10% aq. HC1 solution. The layers were separated, and the organic layer was washed with sat. NaHCOa solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried over Na₂SO4. filtered and concentrated under reduced pressure. Chromatography of residue afforded 594-1 (147 mg, 26%) as a colorless oil. LCMS: m/z 345.15 [M+H]⁺.

[1348] To a stirring mixture of 594-1 (147 mg, 0.45 mmol) in DCM (1.5 mL) at 0 °C were added CBzCl (114 mg, 0.67 mmol) and DIPEA (233 μΙ.. 0.49 mmol). The mixture

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PCT/US2014/051642 was warmed to r.t. for 10 mins. The reaction was quenched with a cold sat. NaHCO₃ solution. The aqueous layer was extracted with DCM, dried over NajSCC. Filtered and concentrated under reduced pressure. Chromatography of the residue afford 594-2 (110 mg,

57%) as a white solid.

[1349] To a stirring mixture of 594-2 (110 mg. 0.25 mmol) in THF (762 pL) at rt was added dropwise a solution of TBAF (0.85 mL) in THF. The mixture was stirred at r.t. until the starting material was consumed. Silica gel was added, and the mixture was stirred at r.t. for 10 mins. resulting mixture was concentrated under reduced pressure. Chromatography of the residue 594-3. w hich was used without further purification. LCMS: m/z 365.05 [M+H]⁺.

[1350] To a stirring mixture of 594-3 (110 mg, -0.3 mmol) in CH2CI2 (1.3 mL) at r.t. was added and Dess-Martin periodinane (383 mg, 0.9 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a 5% Nal ISO ; solution and a sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2 x 25 111L). The organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 594-4 (90 mg, 55% 2 steps). TCMS: m/z 363.05 [M+H]⁺.

[1351] To a stirring mixture of 594-4 (90 mg, 0.248 mmol) in DMF (0.5 mL) were added TMSCF₃ (53 mg, 0.37 mmol) and a TBAF solution in THF (37 pL). The mixture was stirred at r.t. for 1 h. Silica gel was added, and the mixture was stirred for 10 mins. The crude mixture was concentrated under reduced pressure. Chromatography of the residue afford 594-5 (86 mg, 80%). LCMS: m/z 433.05 [M+Hf.

[1352] To a stirring mixture of 594-5 (86 mg, 0.198 mmol) in CH7CI2 (LO mL) at r.t. was added the Dess-Martin periodinane reagent (421 mg. 0.99 mmol). The mixture was stirred at r.t. until the alcohol was consumed. The reaction was quenched with a 5% aqueous solution of NaHSO₃ and a sat. NaHCO₃ solution. The aqueous layer was extracted with EtOAc (2 x 25 mL). The organic layers were dried with Na2SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 594-6 (80 mg. 90%). LCMS: m/z 449.05 [M+H₂O+H]⁺.

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PCT/US2014/051642 [1353] To a stirring mixture of 594-6 (30 mg, 0.074 mmol) in MeNO? (0.5 mL) was added TEA (20 id.. 0.147 mmol). The mixture was stirred at r.t. for 30 mins, and then diluted with DCM and washed with water. The aqueous layer was extracted with DCM, dried over Na?SO₄, flittered and concentrated under reduced pressure. Chromatography of the residue afford 594-7 (30 mg. 82%) as a white solid. LCMS: m/z 492.05 [M+H]⁺.

[1354] To a stirring mixture of 594-7 (30 mg. 0.061 mmol) in EtOAc (0.3 mL) at r.t. was added SnCl₂.2H₂0 (166 mg, 0.74 mmol). The mixture was heated at reflux for 1 h and then cooled to r.t. The mixture was concentrated under reduced pressure. The crude product mixture was direclty loaded into a silica gel column to afford 594-8. LCMS: m/z 462.05 [M+H]⁺.

[1355] To a stirring mixture of 4-cyclopropoxy-3-methoxybenzoic acid (12.6 mg. 0.06 mmol) in DMF (0.5 mL) were added HATU (23 mg. 0.06 mmol) and DIPEA (16 pL. 0.09 mmol). The mixture was stirred at r.t. for 10 mins. A solution of 594-8 in DMF (0.2 mL) was added, and the mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. NallC()_; solution(10 mL). The mixture was diluted with DCM and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford benzyl (2-(2-chloro-6-(3-(4-cyclopropoxy-3-methoxvbenzamido)-1.1,1 -trifluoro-2hydroxypropan-2-yl)-3-methoxypyridin-4-yl)propan-2-yl)carbamate (30 mg, quantitative) as a w⁷hite solid. LCMS: m/z 652.15 [M+H]⁺.

[1356] To a stirring mixture of benzyl (2-(2-chloro-6-(3-(4-cyclopropoxy-3methoxybenzamido)-l,l ,l-trifluoro-2-hydroxypropan-2-yl)-3-methoxypyridin-4-yl)propan-2yl)carbamate (30 mg, 0.046 mmol) in DME (2 mL, deoxygenated prior to using) were added 4-fluorophenyl boronic acid (8 mg, 0.055 mmol), a solution of CS2CO3 (45 mg, 0.14 mmol in 0.3 mL of water) and PdCl₂(dppf) (5 mg. 0.007 mmol). The mixture was stirred at 110 °C under microwave reaction conditions for 1 h. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture w⁷as purified via a silica gel chromatography to afford the product and unreacted starting material (25 mg). LCMS: m/z 712.20 [M+H]⁺.

[1357] To a stirring solution of N-Cbz protected amine and unreacted starting material from the previous step (25 mg) in EtOAc:i-PrOH:HOAc (5 mL:l mL:l 111L) w⁷as

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PCT/US2014/051642 added Pd/C (20 mg). The mixture was placed under a II· balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture was filtered through a plug of celite, and the plug was washed with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure. The crude product mixture was purified via HPLC to afford 594 as a white solid. LCMS: m/z 578.15 [M+H]⁺.

EXAMPLE 383

Preparation of Compounds 582, 583 and 589

N H [1358] To a stirred solution of 582-1 (50 g, 310 mmol) in anhydrous THF (1.2 L) was added LDA (310 mL. 620 mmol) at -78 °C under Nj. The mixture was stirred at -78 °C for 0.5 h. A solution of dimethyl carbonate (67.1 g, 750 mmol) in dry⁷ THF (150 mL) was added dropwise. The solution was wanned to 0 °C and stirred for 1 h below 0 °C. The reaction was quenched with aq. NH4CI (500 mL), extracted with EA (3 x 1 L). The combined organic phase was washed with a. sodium bicarbonate (1 L) and brine, and dried over sodium sulfate. The organic layer was concentrated to dryness, and the residue was

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PCT/US2014/051642 purified by column chromatography (PE:EA = 20:1) to give 582-2 (50 g, 73.5 %) as a colorless oil.

[1359] To a solution of crude 582-2 (50 g, 230 mmol) in dioxane:H₂O (6:1) (1 L) was added 4-fluoro-3-chloro-phenyl boronic acid (40 g, 230 mmol), CS2CO3 (223.3 g, 680 mmol) and Pd(dppf)Cl₂ (16.8 g. 23 mmol) under N2. The mixture was degassed (3x) and refilled with N₂. The mixture was stirred at 80 °C in a pre-heated oil bath for 4 h. After cooling to r.t.. the mixture was diluted with water (1.5 T) and extracted with EA (3 x 1 L). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=20:l~15:l) to yield 582-3 (42 g, 58.7%) as a light yellow⁷ solid.

[1360] To a solution of 582-3 (10 g, 31.9 mmol) in anhydrous THE (100 mL) w⁷as added LiHMDS (63.9 mL, 63.9 mmol) dropwise at -78 °C. The mixture was stirred at -78 °C for 30 mins. A solution of Mel (9.07 g, 63.9 mmol) in dry⁷ THF (50 mL) w⁷as added dropwise. The mixture was w⁷armed to 0 °C and stirred at 0 °C for 1 h. The reaction was quenched with water (100 mL) and extracted with EA (3 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=10:l) to yield 582-4 (3.5 g, 32%) as a light yellow solid.

[1361] To a solution of 582-4 (3.2 g, 10.22 mmol) in anhydrous THF (20 mL) was added NaHMDS (20.44 mL. 20.44 mmol) dropwise at -78 °C. The mixture was stirred at -78 ^l’C for 30 mins. A solution of BnOCH₂Cl (3.19 g, 20.44 mmol) in dry THF (10 mL) was added dropwise. The mixture was warmed to 0 °C and stirred for 1 h. The reaction was quenched with water (50 mL) and extracted with EA (3 x 50 mL). The combined organic layers w^rere washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=10:l) to yield 582-5 (2.7 g, 59%) as a yellow⁷ oil.

11362] To a stirred solution of 582-5 (16.22 g, 36.29 mmol) in anhydrous THF (150 mL) was added L1AIH4 (1.38 g. 36.29 mmol) powder in portions under N₂ at 0 °C for a period of 10-15 mins. The mixture w⁷as stirred at 0 °C for 0.5 h. The reaction w⁷as quenched with w⁷ater (100 mL) and filtered via a plug of celite. The filtrate w⁷as extracted with EA (3 x

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PCT/US2014/051642

100 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=3:1) to give 582-6 (13.5 g, 89 %) as a yellow oil.

[1363] To a stirred solution of 582-6 (5 g, 11.93 mmol) in anhydrous DCM (50 mL) was added FeCfi (19.4 g. 119.3 mmol) powder in one portion at r.t. The mixture was stirred at r.t. for 1 h. The mixture was diluted with water (100 mL) and filtered via a bed of celite bed. The filtrate was extracted with EA (2 x 150 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuum to dryness. The residue was purified by column chromatography (PE:EA=1:1) to give 582-7 (3.6 g, 92 %) as a brown oil.

[1364] To a stirred solution of 582-7 (3.5 g, 10.6 mmol) in anhydrous DCM (20 mL) was added TEA (5.4 g, 53 mmol) at r.t. MsCl (4.8 g, 42.4 mmol) was added dropwise, and the mixture w^ras stirred at r.t. for 1 h. The solution was washed with water (20 mL) and brine (20 mL), and then concentrated to dryness. The residue w^ras purified by column chromatography (PE:EA=5:1) to give 582-8 (3.6 g. 69%) as a yellow oil.

[1365] 582-8 (480 mg, 0.987 mmol) was dissolved in benzyl amine (3 mL). The mixture was heated under microwave irradiation at 135 °C for 5 h. The crude mixture was cooled to r.t. and directly loaded into a silica gel column to afford a mixture of products. This mixture was further purified via prep-HPLC to afford 582-9 (100 mg, 25% yield) as a colorless oil: LCMS: m/z 401.05 [M+H]⁺.

[1366] To a stirring mixture of 582-9 (100 mg. 0.249 mmol) in DME (2 mL. deoxygenated prior to using) were added 4,4,6-trimethyl-2-(3.3,3-trifluoroprop-l-en-2-yl)1,3,2-dioxaborinane (111 mg. 0.498 mmol), a solution of CS2CO3 (243 mg, 0.75 mmol in 0.5 mL of water) and PdCb(dppf) (36 mg, 0.005 mmol). The mixture was stirred at 110 °C for 2 h under microwave reaction conditions. The crude product mixture was diluted w ith EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture was purified via a silica gel chromatography to afford 582-10 (114 mg, quantitative yield), LCMS: m/z 461.05 [M+H]⁺.

[1367] To a stirring mixture of 582-10 (26 mg, 0.056 mmol) in t-BuOH:water (3:1, 1.3 mL total volume) at r.t. were added potassium osmate dihydrate (3 mg. 0.008 mmol)

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PCT/US2014/051642 and tert-butyl tosyloxycarbamate (32 mg, 0.112 mmol). The mixture was stirred at r.t.

overnight. The mixture was diluted with water and diluted with DCM. The aqueous layer was extracted with DCM. dried over NasSOq, filtered and concentrated under reduced pressure. The crude product mixture was purified via a silica gel chromatography to afford

582-11 (15 mg. 45%). LCMS: m/z 594.2 [M+H]⁺.

[1368] The N-Boc protected amine was dissolved in HC1 in dioxane (3 mL, 4N). The mixture was stirred at r.t. for several hours until the starting material was consumed. The crude product was concentrated under reduced pressure and directly used in the next step without further purification. Coupling of the crude amine with 4-cyclopropoxy-3methoxybenzoic acid following the general procedure for 598 afforded 589 as a white solid. LCMS: m/z 684.20 [M+H]⁺.

[1369] To a stirring solution of 589 (38 mg, 0.064 mmol) in EtOAc:iPrOH:HOAc (5 mL:l mL:lmL) w^ras added a 10% Pd/C (40 mg). The mixture was placed under a IE balloon. The mixture was stirred for several hours until the starting material was consumed. The crude mixture w^ras filtered through a plug of celite, and the plug was washed with EtOAc (2 x 20 mL). The mixture was concentrated under reduced pressure and purified via prepHPLC to afford 583 and 582. 583: LCMS: m/z 560.15 [M+H]⁺ and 582: LCMS: m/z 594.15 [M+II] /

EXAMPLE 384

Preparation of Compound 590 [1370] Compound 590 was prepared following the general procedure for 583 using (R)-4-(2-hydroxypropoxy)-3-methoxybenzoic acid and HATU. LCMS: m/z 578.15 [M+H]⁺.

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EXAMPLE 385

Preparation of Compound 584

[1371] 584-1 was prepared following the general procedure for 583 using 3methoxy-4-(2-((4-methoxybenzyl)oxy)ethoxy)benzoic acid and HATU.

[1372] To a stirring mixture of 584-1 in DCM (1 mL) was added TFA (0.2 mL). The mixture was stirred at r.t. for 5 mins, and then diluted with DCM. The reaction quenched with a cold NaHCO₃ solution. The aqueous layer was extracted with DCM. dried with Na₂SO4, filtered and concentrated under reduced pressure. The crude product mixture was purified via prep-HPLC to afford 584 as a white solid. T>CMS: m/z 606.25 [M+H]⁺.

EXAMPLE 386

588-1

[1373] To a stirring mixture of 2-(2-chloro-6-(3-chloro-4-fluorophenyl)pyridin-4yl)propan-2-amine (200 mg. 0.67 mmol) in DCE (1 mL) at r.t. were added acetone (78 mg, 1.33 mmol), HOAc (10 mg) and Na(OAc)₃BH (280 mg). The mixture was stirred at r.t. overnight. The mixture was diluted with DCM, and the reaction quenched with a cold NaHCOj solution. The aqueous layer was extracted with DCM, dried with Na₂SO4, filtered

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PCT/US2014/051642 and concentrated under reduced pressure. The crude product mixture was purified via a silica gel column to afford 588-1 (180 mg. 79%) as a colorless oil. LCMS: m/z 341.0 [M+I I] / [1374] Compound 588 was prepared following the general procedure for 582 and

583. LCMS: m/z 607.2 [M+H]⁺.

EXAMPLE 387

Preparation of Compound 597

nh₂ [1375] To a stirring mixture of 4-(3-hydroxycyclobutoxy)-3-methoxybenzoic acid (70 mg, 0.168 mmol) in DMF (1 mL) were added HATLJ (64 mg, 0.168 mmol) and DIPEA (60 pL, 0.336 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 597-1 in DMF (0.5 mL) was added, and the mixture was stirred at r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCOj (1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford 597-2 (80 mg, 75%) as a white solid. LCMS: m/z 636.15 [M+H]⁺.

[1376] To a stirring mixture of 597-2 (40 mg. 0.063 mmol) in DME:EtOH:H₂O (1.5 mL:0.5 mL:0.2 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (9 mg, 0.063 mmol), K3PO4. 7H₂O (64 mg, 0.19 mmol), KH2PO4 (25 mg. 0.16 mmol) and PdCl₂(dppf) (7.5 mg. 0.01 mmol). The mixture was carried out under microwave irradiation at 110 °C for 5 h. The crude product mixture was diluted with EtOAc and water. An aqueous workup with EtOAc was followed. The crude product mixture was purified via a silica gel chromatography to afford 597-3. LCMS: m/z 696.20 [M+H]⁺.

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PCT/US2014/051642 [1377] To a stirring mixture of 597-3 in MeOH (5 mL) at r.t. was added a solution of IIC1 in dioxane (4N, 1 mL). The mixture was stirred for 10 mins, and then concentrated under reduced pressure. The crude product was purified via HPLC to afford 597 (30 mg,

70%) as a white solid. LCMS: m/z 592.1 [M+H]⁺.

EXAMPLE 388

Preparation of Compound 574

[1378] To a stirring mixture of 574-1 (130 mg. 0.21 mmol) in THF (2 mL) at r.t. was added dropwsse a solution of MeMgBr in toluene (0.91 mL, 1.27 mmol). The mixture was stirred at r.t. for 2 h. and then diluted with EtOAc. The reaction quenched with a sat. NH4CI solution. The layers were separated, and the aqueous layer w'as extracted with EtOAc. The combined organic layers were washed with brine, dried over NiaSOi. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford a mixture that included 574-2. LCMS: m/z 628.20 [M+H]⁺.

[1379] 574-2 (40 mg) was hydrogenated over 10% Pd/C (35 mg) in EtOAc:EtOH (5 mL each) for 2 h. The catalyst was removed by filtration, and the crude product was used in the next step without further purification. LCMS: m/z 594.25 [M+H]⁺.

[1380] To HCl in dioxane (5 mL, 4N) was added 574-3 (20 mg), and the mixture was stirred at r.t. for 3 h. The mixture was concentrated, and the crude product was purified by prep-HPLC to provide 574. LCMS: m/z 494.20 [M+H]¹.

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EXAMPLE 389

Preparation of Compound 572

[1381] To a stirring mixture of 572-1 (25 mg. 0.0357 mmol) in pyridine (1 mL) was added a solution of isopropylchloroformate (110 pL, 0.101 mmol) in toluene. The mixture was stirred at r.t. for 2 h. The mixture was diluted with DCM. and the reaction quenched with a sat. NaHCO?, solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 572-2 as a colorless oil. LCMS: m/z 786.25 [M+H]⁺.

[1382] To a stirring mixture of 572-2 (22 mg, 0.032 mmol) in AcCN (1 mL) at 0 °C were added Nal (24 mg, 0.15 mmol) and TMSC1 (25 pL. 0.15 mmol). The mixture was stirred for an 10 mins, and then warmed to r.t. The mixture was diluted with EtOAc and washed with a 10% aq. Na₂S₂O₃ solution. The organic layer were washed with brine, dried over Na₂SO4, filtered and concentrated under reduced pressure. The mixture was concentrated, and the crude product purified by prep-HPLC to provide 572. LCMS: m/z 686.2 [M+H]⁺.

EXAMPLE 390

Preparation of Compound 591

[1383] To a stirring mixture of 544 (50 mg, 0.075 mmol) in HOAc:EtOAc (6 mL, 5:1) was added Pd/C (30 mg). The mixture was placed under a H₂ balloon for several hours. The mixture was filtered through a plug of Celite, and the plug was washed several times

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PCT/US2014/051642 with EtOAc. The titrate was concentrated under reduced pressure and purified via prepHPLC to afford 544. LCMS: m/z 582.10 [M+II]'/

EXAMPLE 391

Preparation of Compound 640

nh₂ [1384] Suzuki coupling of 640-1 (50 mg) with 4-chlorophenylboronic acid followed by sulfmamide hydrolysis afforded 640 (20 mg) as a white solid. LCMS: m/z 582.15 [M+H]⁺.

EXAMPLE 392

Preparation of Compound 646

OH O' OH O'

NH₂ [1385] Compound 646 (white solid. 11.6 mg) was prepared following the general procedure for 640 using 646-1 (25 mg). LCMS: m/z 596.10 [M+H]⁺.

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EXAMPLE 393

Preparation of Compound 666

[1386] Compound 666 (white solid. 6.7 mg) was prepared following the general procedure for 640 using 646-1 (20 mg) and 4-chloro-3-fluorophenvl boronic acid. LCMS: m/z 614.15 [M+H]⁺.

EXAMPLE 394

Preparation of Compound 649

[1387] Compound 649 (white solid. 19.6 mg) was prepared following the general procedure for 640 using 640-1 (40 mg) and (6-oxo-1.6-dihydropyridin-3-yl)boronic acid.

LCMS: m/z 565.15 [M+H]⁺.

EXAMPLE 395

Preparation of Compound 665

[1388] Compound 649 (white solid, 9.2 mg) was prepared following the general procedure for 640 using 646-1 (35 mg) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid. LCMS: m/z 648.15 [M+H]⁺.

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EXAMPLE 396

Preparation of Compound 628

[1389] To a stirring mixture of methyl-4-methoxybenzoate (1 g, 5.49 mmol) in DMF (5 mL) at r.t. was added K.2CO3 (1.14 g, 8.24 mmol) and 2-bromoacetonitrile (653 mg, 5.49 mmol). The mixture was stirred at r.t. for 3 h, and then diluted with EtOAc and water. The aqueous layer was extracted with EtOAc. The organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-1 as a white solid.

[1390] To a stirring mixture of 628-1 (600 mg, 2.72 mmol) in THF (6 mL) was added dropwise a solution of borane and DMS complex in THF (0.26 mL, 2.72 mmol) at r.t. The mixture was slowly warmed to 60 °C for 1 h. The mixture was cooled to r.t. and diluted with EtOAc. The reaction was quenched with an aq. solution of HCI (IN). The mixture was stirred at r.t. for 10 mins and then neutralized with a sat. NaHCO₃ solution. The layers were separated, and the aquoues layer was extracted with EtOAc. The organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-2 as a white solid. LCMS: m/z 226.1 [M+H]⁺.

[1391] To a stirring mixture of 628-2 (40 mg, 0.177 mmol) in DCM (0.6 mL) at 0 °C were added diphosgene (32 mg, 0.177 mmol) and DIPEA (42 pL. 0.27 mmol). The

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PCT/US2014/051642 mixture was warmed to r.t. for 20 mins and then concentrated under reduced pressure. The crude product was dissolved in toluene (0.5 mL), and azidotrimcthylsilane (0.14 mL) and 1 drop of BF₃. Oil? were added. The mixture was heated at reflux for 1 h. The crude mixture was cooled to r.t. and diluted with DCM. The reaction was quenched with water, and extracted with DCM. The organic layers were dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 628-3 as a white solid (18 mg, 36% in 2 steps).

[1392] 628-3 was dissolved in a solution of HCI in dioxane (1 mL). An aqueous solution of HCI (6N, 1 mL) was added, and the mixture was heated at 80 °C overnight. The mixture was cooled to r.t. and diluted with EtOAc. The aqueous layer was extracted with EtOAc. The organic layers were dried over Na₂SO4. filtered and concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford 628-4 as a white solid. LCMS: m/z 302.85 [M+Naf.

[1393] To a stirring mixture of tert-butyl (2-(2-(3-amino-1.1,1 -trifluoro-2hydroxypropan-2-yl)-6-(3-chloro-4-fluoroplienyl)pyridin-4-yl)propan-2-yl)carbamate (8 mg, 0.0163 mmol) and 628-4 (from the previous step) in DCM (0.3 mL) were added EDC1 (6.2 mg, 0.032 mmol). HOAt (4.5 mg, 0.033 mmol) and TEA (20 pL). The mixture was stirred for 5 mins, and the reaction was quenched with 2 drops of a solution of HCI (IN). The organic layer was transferred to a different flask and concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford the desired product as a white solid; LCMS: m/z 754.20 [M+H]⁺.

[1394] 628-5 was dissolved in a solution of HCI in dioxane (5 mL, 4N). The mixture was stirred at r.t. until the starting material was consumed. The crude mixture was concentrated under reduced pressure and purified via prep-HPLC to afford 628 as a white solid (8.5 mg). LCMS: m/z 654.1 [M+H]⁺.

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EXAMPLE 397

Preparation of Compound 636

[1395] To a stirring mixture of 636-1 (130 mg, 0.192 mmol) in DMF (1 mL) were added added K2CO3 (80 mg, 0.576 mmol) and 2-bromoacetonitrile (46 mg, 0.38 mmol). The mixture was stirred at r.t. until the starting material was consumed. The mixture was diluted with EtOAc and washed with brine. The aqueous layer was extracted with EtOAc, dried over Na₂SO4, filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 636-2 as a colorless oil (40 mg). LCMS: m/z 715.15 [M+H]⁺.

[1396] To a stirring mixture of 636-2 (20 mg, 0.028 mmol) in pyridine (0.3 mL) was added NH₂OH*HCI (10 mg). The mixture was stirred at reflux for several hours. The mixture was cooled to r.t., diluted with toluene and concentrated under reduced pressure. This process w'as repeated twice. The crude product was purified via a silica gel column to afford 636-3 as a colorless oil (10 mg).

11397] To a stirring mixture of 636-3 (10 mg, 0.013 mmol) in

EtOAc:HOAc:EtOH (5:1:1, 7 mL) was added Pd/C (20 mg). The mixture w^ras placed under a H₂ balloon for several hours. The mixture was filtered through a plug of Celite, and the plug was washed several times with EtOAc. The titrate was concentrated under reduced pressure and purified via prep-HPLC to afford 636 (4.0 mg) as a white solid. LCMS: m/z 580.15 [M+H]⁺.

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EXAMPLE 398

Preparation of Compound 652

[1398] To a stirring mixture of 652-1 (750 mg. 2.12 mmol) were added 1chlorohex-5-en-2-one (390 mg, 2.33 mmol) and potassium carbonate (410 mg, 2.97 mmol) in acetone (4.0 mL). The mixture was stirred at 50 °C for 2 h. The volatiles were removed under reduced pressure, and the residue was partitioned between water and EtOAc. The layers were separated, and the organic layers were dried with Na₂SO4. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-2 as a white solid (480 mg. 50%). LCMS: m/z 449.90 [M+H]⁺.

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PCT/US2014/051642 [1399] A mixture of 652-2 (420 mg, 1.18 mmol), 2-methylpropane-2-sulfinamide (157 mg, 1.31 mmol) and titanium(IV) ethoxide (770 pL, 2.6 mmol) in THF (7 mL) was heated to 70 °C (sealed vial, degassed and purged with N₂). The mixture was stirred 70 °C for 3 h. The mixture was diluted with EtOAc and w'ater was added. The mixture was stirred for 5 mins and then filtered through a pad of celite. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried with hwuSO-i and filtered. The volatiles were removed under reduced pressure. Crude 652-3 was used in the next step without further purification. LCMS: m/z 552.95 [M +H]⁺.

[1400] n-Buthyllithium (2.5 M solution in hexane, 0.64 mL, 1.6 mmol) was added to a solution of ethylmagnesium bromide (3.42 M in 2-Me THF, 0.24 mL, 0.8 mmol) in THF (2.5 mL), which had been pre-cooled to 0°C. After 10 mins, the mixture was cooled to -78 °C. A solution of 652-3 (460 mg, 0.83 mmol) in THF (1 mL) was added dropwise, and the mixture was stirred at -78 °C for 15 mins. The reaction was quenched with MeOH and diluted with EtOAc. The organic layer was washed with brine, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na₂SO₍, filtered and concentrated under reduced pressure. Chromatography of the residue afforded 652-4 as a brownish oil. LCMS: m/z 427.05 [M+H]⁺.

[1401] To a stirring mixture of 652-4 (180 mg, 0.42 mmol) in DCM (2 mL) was added Dess-Martin reagent (537 mg, 1.26 mmol). The mixture was stirred at r.t. until the starting material was consumed. The mixture was diluted with EtOAc. The reaction quenched with 5% of NaHSO₃ and a sat. NaHCO₃ solution. The layers were seperated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na₂SO4. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 652-5 as a white solid. LCMS: m/z 443.1 [M+H+H₂O]⁺.

[1402] To a stirring mixture of 652-5 (135 mg, 0.305 mmol) in nitromethane (0.5 mL) at r.t. was added TEA (63 pL. 0.46 mmol). The mixture was stirred at r.t. for 30 mins and then diluted with DCM. The reaction was quenched with a sat. NaHCO₃ solution. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure.

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The crude product was purified via a silica gel column to afford 652-6 as a white solid (140 mg, 94%). LCMS: m/z 486.05 [M+11]¹.

[1403] To a stirring mixture of 652-6 (50 mg, 0.1 mmol) in EtOH:water (10:1, 1.1 mL) was added Fe (28 mg. 0.5 mmol) and NH4CI (27 mg. 0.5 mmol). The mixture was heated at 80 °C for 30 mins and thens cooled to r.t. The mixture was diluted with DCM (5 mL). and the reaction was quenched with a solution of NaOH (2N. 1 mL). The layers were separated, and the aqueous layer was extracted with DCM (2x5 mL). The combined organic layers were dried over Na2SO₄, filtered and concentrated under reduced pressure. The erode product was purified via a silica gel column to afford 652-7 as a white solid. LCMS: m/z 456.1 [M+H]⁺.

11404] To a stirring mixture of 3-methoxy-4-(2-((4methoxvbenzyl)oxy)ethoxy)benzoic acid (14.5 mg. 0.044 mmol) in DMF (0.2 mL) were added HATU (17 mg, 0.044 mmol) and DIPEA (17 μΐ.. 0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 652-7 (20 mg. 0.044 mmol) in DMF (0.1 111L) was added, and the mixture was stirred at for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO₃ (1 mL). The mixture was diluted with DCM. and an aqueous work up with DCM was followed. The crude product was purified via prep-HPLC to afford 652-8 (6.5 mg, 19%) as a white solid. LCMS: m/z 770.25 [M+H]~.

[1405] To a stirring mixture of 652-8 (6.5 mg, 0.008 mmol) in DME:EtOH:H₂O (1.0 mL:0.3 mL:0.1 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (9 mg, 0.063 mmol), Ι<₃ΡΟ₄·7Η₂Ο (14.3 mg, 0.04 mmol), KH₂PO₄ (5.5 mg, 0.04 mmol) and PdCl₂(dppf) (6.0 mg, 0.008 mmol). The mixture was carried out under microwave irradiation at 110 °C for 5 h. The crude product was concentrated under reduced pressure and purified via a silica gel chromatography to afford 652-9. LCMS: m/z 830.2 [M+H]⁺.

[1406] To a stirring mixture of 652-9 in t-BuOH:H?O (3:1, 0.4 mL) were added K₂OsO₄«2H₂0 (1 mg). The mixture was stirred for 2 h and NaIO₄ (5 mg) was added. The mixture was stirred at r.t. overnight. The mixture was loaded directly into a silica gel column to afford 652-10. LCMS: m/z 832.3 [M+H]⁺.

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PCT/US2014/051642 [1407] To a stirring mixtue of 652-10 in MeOH (1.0 mL) was added a solution of IIC1 in dioxane (0.2 mL). The mixture was stirred for 10 mins at r.t. and concentrated under reduced pressure. Crude 652-11 was used in the next step without further purification.

[1408] 652-11 was dissolved in MeOH (0.5 mL) was added NaBH₄ (1.6 mg).

The mixture was stirred at r.t. for 10 mins and then diluted with EtOAc. The reaction was quenched with a sat. Nal ICO; solution. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na?SO4. filtered and concentrated under reduced pressure. Crude 652-12 was used in the next step without further purification.

[1409] To a stirring mixture of 652-12 in DCM (1.0 ml.) was added TFA (0.1 mF). The mixture w⁷as stirred at r.t. until the starting material was consumed. The mixture was diluted with DCM, and the reaction was quenched with a cold sat. NaHCOj solution. The layers were separated, and the aqueous layer w⁷as extracted with EtOAc. The The combined organic layers w⁷ere dried over NasSOq. filtered and concentrated under reduced pressure. The crude product w⁷as purified via prep-HPLC to afford 652 as a while solid (1.0 mg). LCMS: m/z 592.20 [M+H]⁺.

EXAMPLE 399

Preparation of Compound 645

o

nh₂ [1410] 645-2 was prepared following the general procedure for 635-2. LCMS:

m/z 610.10 [M+H]⁺. 645-3 was prepared following the general procedure for 635-3. LCMS:

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PCT/US2014/051642 m/z 720.20 [M+H]⁺. Compound 645 (15.7 mg) was prepared following the general procedure for 635 using 645-3 (45 mg, 0.063 mmol). LCMS: m/z 616.15 [M+I I]⁺.

EXAMPLE 400

Preparation of Compound 662

[1411] Compound 662 (5.7 mg) was prepared following the general procedure for 645. LCMS: m/z 616.10 [M+H]⁺.

EXAMPLE 401

Preparation of Compound 663

nh₂ [1412] Compound 663 (11.4 mg) was prepared following the general procedure for 645. LCMS: m/z 584.15 [M+H]⁺.

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EXAMPLE 402

Preparation of Compound 647 \ /

Si-

nh₂ [1413] 647-3 was prepared following the general procedure for 635-3. LCMS:

m/z 839.25 [M+H]⁺. 647-4 was prepared following the general procedure for 635. 647-4 (51 mg, 0.084 mmol) was treated with TBAF (IM in THF, 0.1 mL, 0.1 mol) in THF (2 mL) at 70 °C for 2 h. The mixture was concentrated, and the crude product purified by silica gel chromatography (C^CHMeOHNHj) to provide 647 (10 mg, 19%). LCMS: m/z 605.15 [M+H]⁺.

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EXAMPLE 403

Preparation of Compound 648

[1414] 648-2 was prepared following the general procedure for 637-4. LCMS:

m/z 629.05 [M+H]⁺. 648-3 was prepared following the general procedure for 635-3. LCMS: m/z 719.15 [M+H]⁺. Compound 648 (13.5 mg) was prepared following the general procedure for 635 using 648-3 (27 mg, 0.038 mmol). LCMS: m/z 615.15 [M+H]⁺.

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EXAMPLE 404

Preparation of Compound 651

[1415] 651-2 was prepared following the general procedure for 637-2. LCMS:

m/z 730.20 [M+H]⁺. 651-3 was prepared following the general procedure for 637-3. LCMS: m/z 787.30 [M+HJ¹.

[1416] A solution of 651-3 (15 mg, 0.019 mmol) in CEfCN (0.5 mL) was added dropwise to a solution of isopentyl nitrite (4 uL, 0.029 mmol) and copper bromide (3 mg. 0.023 mmol) in CH3CN (1 mL) at 65 °C. The mixture was stirred at 65 °C for 1 h and then cooled to 0 °C. The reaction was quenched with the addition of IN HC1. The aqueous layer was basified with sodium bicarbonate and extracted with EA. The product was used without further purification to provide 651-4. LCMS: m/z 748.15 [M+H]⁺.

[1417] Trifluoroacetic acid (0.1 mL) was added to a solution of 651-4 in CH2CI2 (0.9 mL), and the reaction was stirred at r.t. for 5 mins. The mixture was cooled to 0 °C. The reaction was quenched with bicarbonate and extracted with EA. The product was purified by reverse-phase HPLC to yield 651 (4.0 mg). LCMS: m/z 628.05 [M+H]⁺.

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EXAMPLE 405

Preparation of Compound 661

[1418] Compound 661 was prepared following the general procedure for 651. LCMS: m/z 563.15 [M+H]⁺.

EXAMPLE 406

Preparation of Compound 493

[1419] Compound 493 was prepared following the general procedure for 397 using (S)-3-methoxy-4-((2-oxopyrrolidin-3-yl)oxy)benzoic acid. [M+H]'.

LCMS: m/z 640.15

EXAMPLE 407

Preparation of Compound 587

[1420] To a stirring mixture of 587-1 (200 mg, 0.67 mmol) in DCE (1 mL) at r.t.

were added acetone (78 mg. 1.33 mmol), HOAc (10 mg), and Na(OAc)3BH (280 mg). The

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PCT/US2014/051642 mixture was stirred at r.t. overnight. The mixture was diluted with DCM, and the reaction was quenched with a cold NaHCOs solution. The aqueous layer was extracted with DCM, dried over Na₂SO4. filtered and concentrated under reduced pressure. The crude product was purified via a silica gel column to afford 587-1 (180 mg. 79%) as a colorless oil. LCMS: m/z

341.0 [M+H]⁺.

[1421] Compound 587 (35 mg) was prepared in 4 steps from 587-2 (180 mg). LCMS: m/z 641.15 [M+H]⁺.

EXAMPLE 408

Preparation of Compound 664

[1422] Compound 664 is a single diastereomer of 626 and was obtained by chiral separation of 626 via SFC system. +ESI-MS: m/z 570.15 [M+H]⁺ .

EXAMPLE 409

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PCT/US2014/051642 [1423] To a stirring mixture of 642-1 (540 mg, 1.76 mmol) in DMF (5 mL, deoxygenated prior to use) were added Pd(OAc)? (119 mg, 0.17 mmol), PPh₃ (102 mg, 0.387 mmol), TEA (0.3 mL, 2.11 mmol) and ethyl acrylate (0.42 mL, 3.87 mmol). The mixture was stirred at 85 °C overnight. The mixture was diluted with EtOAc and washed with brine. The layers were separated, and the aqueous layer was extracted with EtOAc. The organic layers were dried over AToSO μ filtered and concentrated under reduced pressure. The crude product was purified via a silica gel chromatography to afford 642-2 as a yellow solid (410 mg, 83%). LCMS: m/z 280.05 [M+H]⁺.

[1424] To a stirring mixture of 642-2 in a solution of HCl in dioxane (3 mL) was added concentrated HCl (1 mL). The mixture was stirred at 90 °C overnight. The crude product was cooled to r.t. and concentrated under reduced pressure to afford 642-3 as a brown solid. The solid was dissolved in toluene and concentrated under reduced pressure (2X). Crude 642-3 was used in the next step without further purification. LCMS: m/z 220.0 [M+H]⁺.

[1425] To a stirring mixture of 642-3 (63 mg, 0.144 mmol) in DMF (0.5 mL) were added EDC1 (33 mg, 0.173 mmol). HO At (23 mg, 0.173 mmol) and TEA (41 pL. 0.088 mmol). The mixture was stirred at r.t. for 5 mins. A solution of 642-4 (60 mg, 0.144 mmol) in DMF (0.5 mL) was added. The mixture was stirred r.t. for 10 mins. The reaction was quenched with a 10% aq. solution of NaHCO₃ (1 mL). The mixture was diluted with DCM, and an aqueous work up with DCM was followed. The crude product was purified via prepHPLC to afford 642-5 (20 mg) as a white solid. LCMS: m/z 617.1 [M+H]⁴.

[1426] To a stirring mixture of 642-5 (20 mg, 0.032 mmol) in DME:EtOH:H?O (1.0 mL:0.3 mL:0.1 mL, deoxygenated prior to using) were added 4-fluorophenylboronic acid (9 mg. 0.063 mmol), K₃PO₄. 7ILO (43 mg, 0.128 mmol). KH₃PO₄ (17.4 mg, 0.128 mmol) and PdCli(dppf) (20 mg). The mixture was carried out under microwave irradiation at 110 °C for 5 h. The crude product was concentrated under reduced pressure, and then purified via a silica gel chromatography to afford 642-6 as a brownish oil. LCMS: m/z 677.15 [M+H]⁺.

[1427] To a stirring mixture of 642-6 in MeOH (1 mL) at r.t. was added a solution of HCl in dioxane (0.2 111L, 4N). The mixture was stirred at r.t. for 5 mins and then

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PCT/US2014/051642 concentrated under reduced pressure. The crude product was purified via prep-HPLC to afford 642 (8.5 mg ) as a white solid. LCMS: m/z 573.1 [M+II] .

EXAMPLE 410

Preparation of Compound 476

[1428] Diisopropylazadicarboxylate (0.29 mL, 1.5 mmol) was added to a solution of methyl 3-fluoro-4-hydroxybenzoate (0.21 g. 1.2 mmol, ethyl glycol mono-to7-butyl ether (0.32 mL, 2.5 mmol) and polymer bound triphenylphosphine (1.1 g, 1.9 mmol) in THF (5 mL). The mixture was stirred at r.t. for 1 h. The resin was removed by filtration, and the mixture was concentrated. The product was purified by column chromatography (hexane:EA) to 476-1 (0.34 g, 98%).

[1429] NaOH (2N. 3 mL) was added to a solution of 476-1 (0.34 g, 1.2 mmol) in MeOH (10 mL), and the mixture was heated at reflux for 1.5 h. The mixture was acidified with IN HC1 and extracted with EA. The organic extracts were washed with brine, dried and concentrated to obtain 476-2 (0.29 g, 91%).

[1430] 476-3 was prepared following the general procedure for 635-2 using 4762. 476-4 was prepared following the general procedure for 635-3 using 476-3.

[1431] HC1 (4N in dioxane. 1 mL) was added to a solution of 476-4 (32 mg, 0.049 mmol) in (Ί LCL (1 mL), and the mixture was stirred at r.t. for 5 h. The mixture was concentrated and the crude product purified by HPLC to yield 476. LCMS: m/z 555.05 [M+H]⁺.

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EXAMPLE 411

Preparation of Compound 481

[1432] Compound 481 (8.7 mg) was prepared following the general procedure for 645. LCMS: m/z 562.15 [M+Hf.

EXAMPLE 412 [1433] The following compounds were prepared following one or more of the methods provided herein.

No.	Structure	MS
472	A N- Γ l· 11 H HO R (⁷ Ύ L/L./L nr V ,n. X. γ ci o LA \ o	nd
484	O ,O. .F ^H0 \ Ί η ^F¥ A A LAX, ⁿ \ AA^ ^Ν.·^χΧΧ ° LY HOrA nh₂	568.0 [M+H]⁺
492	0 to- A .to to XX+X-XJ I XI 0 nh₂	567.0 [M+H]⁺
668	X ,0. X .Cl Y Y1 h ^fx^oh AT ⁰ \tox \ ⁰ nh₂	579.2 [M+H]⁺

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No.	Structure	MS
669	Y Y\ A-. /^F ^H0 III η Ύ^Η \ A ⁿ Ax\|/ⁿ AA _------nh₂ F-^F	610.1 [M+Na]⁺
670	Y HO^/vA\|) _H F₃C OH \|Y YA y ^N Αγ ^NyAk 0 L J. \ o nh₂	563 [M+H]⁺
671	Y /0. A / ^H0 r ii h ^fy^oh A kYY/ N ^γγ, N Y/ N ⁰ L J, Y 'o nh₂	563.0 [M+H]⁺
672	Y Ail h^F3C/^oh iAA™ k Jk Y .N. Y, J .....j AA V o ___/ nh₂	578.0 [M+H]⁺
673	Y /-, to, Y OF, ^HO \ Il η YY Γ Y Akk^ ⁿ -^kk^N^^Yi^Y AA ,γ% nh₂	617.1 \|M - H\|
674	Y o ^k. Al HO γ ft _H F₃C OH Y r NH₂ Αγγ/ N .,/kY o L A A> nh₂	591.1 [M+H]⁺

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No.	Structure	MS
675	A o u F₃c OH A/A^OH MyCK/NyU ⁰ Ύ o nh₂	614.0 [M+Na]⁺
676	0 /x O. /x X^F ^H0 I 1 H ^FV^H ΓΎ AwAw^N\/\zⁿvA/ ⁰ Fx +/ nh₂	570.1 [M+I I]'
677	to OH ^ho^z +° ^z' j h/^oh a-a to/tow^N'xto \w^N+toAA o \ P NH^	nd
678	to ^ΗΟ' ·^/0 / ’ _u f₃c oh ⁰ \ o NH₂	nd
679	to /x tox Jx R HO γ \|1 _H F₃C OH / \|[ X/Xw ^N \/X/ ^N-wto+to o totox \ o rW / nh₂	nd
680	to /-x Ό. .x χχ. ,F ^HO Γ 1 H ^F/»^OH ! iT Mto^N\X^^N _vK/ o totox \ P /........Ή / nh₂	nd

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No.	Structure	MS
681	o AN ^F ^HO r ii 1. f₃c oh r ii H \ f O \ / nh₂	nd
682	o AN Λ ^HO \ ll h ^FsC Γ ll ⁰ \ P / nh₂	nd

EXAMPLE A RSV Antiviral Assay [1434] CPE reduction assays are performed as described by Sidwell and Huffman et al., Appl. Microbiol. (1971) 22(5):797-801 with slight modifications. HEp-2 cells (ATCC#, CCL-23) are seeded at a density of 1.500 cells/30 μΙ/well into the 384-well cell plate(s) (Corning#3701) one day prior to the assay. Compounds are added into 384-well cell plates by Labcyte POD 810 Plate Assembler system. Each of the test compounds is provided to duplicate wells of a 384-well cell plate at final concentrations starting from 100 μΜ or 1 μΜ using 1/3 stepwise dilutions for 9 points. Quick-thaw Respiratory Syncytial Virus (RSV) long strain (ATCC#VR-26) stock in a 37°C water bath. Place on ice until ready to use. Viruses are diluted to the concentration of 100 TC1D₃q/30 μΙ. with medium and 30 μΐ diluted RSV are added into related wells of 384-well cell plates. For each plate, sixteen wells are set aside as uninfected, untreated cell controls (CC), and nine wells per test plate receive virus only as a control for virus replication (VC). Lhe final DMSO concentration of all wells is 1%. Place the plates at 37°C, 5% CO? for 5 days.

[1435] After 5 days incubation, observe the CPE of cells in all wells. Cell controls should be natural and have no cell fusion; Cells in the virus control wells should exhibit signs of virus cytopathology (giant cell formation, syncytia). Six μΙ of cell counting kit-8 reagent (CCK-8. Dojindo Molecular Technologies Inc., CK04-20) are added to each well, w'hich

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PCT/US2014/051642 allows colorimetric assays to determine the number of viable cells through the dehydrogenase activity detection. After 3-4 hour incubation, the absorbance of each well is measured with a spectrophotometric plate reader at 450 nm wavelength, using a 630 nm filter as background according to manufacturer's instruction. The 50% effective concentration (EC?o) is calculated by using regression analysis, based on the mean O.D. at each concentration of compound.

[1436] Compounds of Formula (1) are active in the assay against the RSV virus as demonstrated in Tables A and B. Table A includes compounds with an ECjo value that is less than 1 μΜ. Table B includes compounds with an ECso value that is equal to or higher than 1 pM and less than 50 μΜ. Other tested compounds disclosed herein had an EC50 value of 50 μΜ or greater.

Table A

Compound	Compound	Compound	Compound	Compound	Compound
101	176	218	255	298	334
115	181	219	256	299	335
116	182	220	257	303	A < J JO
116b	184	221	258	304	338
117	185	222	259	305	339
117b	189	223	260	308	340
118	191	224	261	309	342
118b	192	226	262	310	343
119	193	227	263	312	344
120	194	228	267	314	345
120b	195	232	270	315	346
122	198	234	272	317	347
122a	199	235	273	318	348
123	200	237	274	320	349
124	202	238	281	321	353
125	204	239	282	322	356
126	205	240	283	323	357
127	208	241	284	324	358
130	209	243	285	325	359
135	210	244	287	326	360
140	211	245	289	327	361
142	212	246	292	328	362
143	213	248	294	330	364
166	214	249	296	1 jj 1	365
167	217	250	297	-> -Ί JJJ	366

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Compound	Compound	Compound	Compound	Compound	Compound
368	431	482	525	562	615
369	433	483	526	563	619
370	434	485	527	565	620
371	435	486	528	568	621
372	436	487	529	569	623b
	442	488	530	570	624b
383	443	489	531	571	626
384	444	490	532	574	627
385	445	491	C -> J	575	628
387	447	494	534	577	629
388	448	495	535	579	630
391	449	496	536	580	631
392	451	497	537	583	632
394	452	498	538	586	633 b
396	453	498d	539	587	634
400	454	499	540	590	635
403	455	500	541	591	638
405	456	501	542	592	640
406	459	502	543	593	642
409	460	503	545	594	643
411	461	504	546	595	644
413	462	505	547	596	645
414	464	507	548	597	646
415	465	508	550	598	650
418	466	510	551	599	653
419	467	514	552	604d	654
421	469	515	553	605a	656
423	470	516	554	605b	662
424	473	517	556	605d	663
425	474	518	557	610	664
426	475	519	558	611	665
428	476	520	559	612	666
429	479	521	560	614	667

Table B

Compound	Compound	Compound	Compound	Compound	Compound
100	109	117a	131	148	175
102	111	118a	132	149	177
104	112	120a	1	150	178
106	113	121	134	161	179
107	114	122b	137	165	196
108	116a	129	145	174	206

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Compound	Compound	Compound	Compound	Compound	Compound
207	266	278	410	478	623a
215	275	279	416	484	624a
216	283	280	417	492	633 a
229	186	286	432	549	637
2dd	187	290	437	561	639
251	190	302	438	604b	655
252	197	3 l D	440	604a	673
253	236	DD /	450	605c
254	268	368	463	607
264	276	404	471	608
265	277	407	477	609

EXAMPLE B

Cytotoxicity Determination [1437] In order to determine the compound cytotoxicity, in parallel, each of the compounds is applied to duplicate wells in a 384-well cell plate at serial final concentrations starting from 100 μΜ using 1/2 stepwise dilutions for 7 points without addition of virus. Incubate the cells at 37°C, 5% CO? for 5 days. Add 6 pL CCK-8 into each well and incubate in a CO? incubator at 37°C for 3-4 hours. Read the plates to obtain the optical densities which are used to calculate 50% cytotoxicity concentration (CC50).

[1438] Compounds of Formula (I) are not cytotoxic as shown in Tables C and D. Table C includes compounds with a CC50 value that is greater than 100 μΜ. Table D includes compounds with a CC50 value that is equal to or less than 100 μΜ and greater than 10 μΜ. Other tested compounds disclosed herein had a CC50 value of less than 10 μΜ.

Table C

Compound	Compound	Compound	Compound	Compound	Compound
108	150	183	199	234	294
109	175	187	205	236	302
116a	176	189	206	244	303
117b	177	190	209	245	304
120	178	191	213	247	η n 1 DD 1
120b	179	192	220	248	335
121	180	194	228	287	345
123	181	195	229	291	π r π D^D
135	182	196	233	292	358

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Compound	Compound	Compound	Compound	Compound	Compound
370	420	474	611	624a	670
“7*1 J / J	421	484	612	624b	671
387	427	492	613	625	672
403	439	561	615	627	673
404	441	562	616	628	674
405	446	580	620	634	675
406	447	604a	621	643
408	451	604b	623a	653
419	470	608	623b	655

Table D

Compound
100
101
102
104
106
107
110
111
112
113
114
115
116
116b
117
117a
118
118a
118b
119
120a
122
122a
122b
124
125
126
127
129
130

Compound
131
132
1
134
137
140
142
143
145
148
149
161
163
165
166
167
174
184
185
186
193
197
200
202
204
207
208
210
211
212

Compound
214
215
216
217
218
219
221
222
223
224
226
227
232
235
237
238
239
240
241
242
243
246
249
250
251
252
253
254
255
256

Compound
257
258
259
260
261
262
263
264
265
266
267
268
269
270
277
278
279
283
285
286
288
289
290
293
295
296
297
298
299
305

Compound
308
309
310
312
j 1 j
315
317
318
320
321
322
326
327
328
330
π 3 J D
334
336
337
338
339
340
342
343
344
346
347
348
349
356

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Compound
357
359
360
361
362
364
365
366
368
369
371
372
383
384
385
386
388
391
392
396
400
407
409
410
411
412
413
414
415
416
417
418
422
423
424
425
426
428
429
430

Compound
431
432
433
434
435
436
437
438
440
442
443
444
445
448
449
450
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
471
473
475
476
477
479

Compound
482
483
485
486
487
488
489
490
491
495
496
498
498d
500
501
502
503
504
507
510
514
515
516
517
518
525
526
527
528
529
530
531
532
ΓΟΊ JJ J
534
535
536
537
538
539

Compound
540
541
542
543
545
546
547
548
549
550
551
552
553
554
556
557
558
559
560
563
565
568
569
570
571
574
575
577
578
579
583
586
587
590
592
593
594
595
596
597

Compound
598
599
604c
605a
605b
605c
605d
606
607
609
610
614
617
619
626
629
630
631
632
633a
633b
635
637
638
639
640
642
644
645
646
650
654
656
662
663
664
665
666

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EXAMPLE C

RSV Polymerase Inhibition Assay [1439] Standard RSV polymerase assays were conducted in the presence of 10 nM recombinant RSV complex in a reaction buffer containing Tris-HCI pH7.5, 6 mM MgCl₂, and other additives and substrates including RNA oligonucleotides and radionucleotides. Standard reactions were incubated in 96-well plate format for 2 h at 30 °C. in the presence of increasing concentration of inhibitor. The reaction was stopped with 90 ul. of 0.1 M EDTA, and the reaction product was transferred to a reading 96-well plate. After washing of the plate, radiolabeled RNA products were detected according to standard procedures with a Trilux Topcount scintillation counter. The compound concentration at which the enzyme-catalyzed rate was reduced by 50% (IC50) was calculated by fitting the data to a non-linear regression (sigmoidal). The IC50 values were derived from the mean of several independent experiments and are shown in Tables E and F.

[1440] Table E includes compounds with an IC50 of < 1 pM. Table F includes compounds with an IC50 <10 pM. Table G includes compounds with an IC50 value of <100 μΜ.

Tabic E

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Compound
250
251
252
254
255
256
257
258
259
260
261
262
263
264
266
267
270
271
272
273
274
275
276
278
279
280
281
282
283
284
285
287
289
292
297
298
299
301
302
303
304
305
306

Compound
307
308
309
310
311
312
314
315
316
317
318
319
320
321
322
323
324
325
326
327
328
329
330
JJ 1
ί in JJZ
~y -> Ί 333
Ο O A j j4
335
336
o -> -7 33 '
338
339
340
341
342
343
344
345
346
347
348
349
353

Compound

354

355

356

357

358

359

360

361

362

364

365

366

367

369

370

371

372

373

375

376

378

379

380

383

384

385

386

387

388

389

390

391

392

393

394

395

396

397

398

399

400

402

403

Compound

405

406

409

411

413

415

418

419

421

423

424

425

428

431

432

434

435

436

437

440

442

443

444

445

447

448

449

451

452

453

454

455

456

459

460

461

462

463

464

465

466

467

469

Compound

470

473

474

475

476

479

481

482

483

485

486

487

488

489

491

493

494

495

496

497

498

498c

498d

499

500

501

502

503

504

505

506

507

508

509

510

511

514

515

516

517

518

519

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Compound		Compound		Compound	Compound	Compound
520	549	581	615	643
521	550	582	617	644
522	551	583	618	645
523	552	584	619	646
524	553	585	620	647
525	554	586	621	648
526	555	588	622	650
527	556	589	623 b	651
528	557	590	624b	652
529	558	591	625	653
530	559	593	626	654
531	560	594	627	655
532	562	595	628	656
533	563	596	629	657
534	565	598	630	658
535	567	599	631	662
536	568	600	632	663
537	569	601	633a	664
538	570	602	633b	665
539	571	603	634	666
540	573	604d	635	667
541	574	605a	636	668
452	575	605c	637	669
543	576	605d	638	676
545	577	610	639
546	578	611	640
547	579	612	641
548	580	614	642
Table F
Compound		Compound		Compound	Compound	Compound
109	153	247	350	477
114	154	253	352	478
120a	165	265	363	480
122b	168	268	377	484
124	174	277	404	490
145	175	286	416	492
146	177	290	417	498b
148	187	294	426	512
149	188	296	438	513
150	203	300	450	561
151	216	j 1 j	471	564

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Compound		Compound		Compound	Compound	Compound
572	604b	609	624a	673
592	604c	613	659
597	607	616	660
604a	608	623a	672
Table G
Compound		Compound		Compound	Compound	Compound
116a	161	230	407	427
117a	178	242	408	430
118a	180	295	412	439
135	186	368	420	441
144	201	382	422	446

EXAMPLE I) RSV Assay [1441] The RSV subgenomic replicon 395 HeLa and APC126 were licensed from Apath (Brooklyn. NY) and were originally developed by Dr. Mark Mceples of Center for Vaccines & Immunity, the Research Institute at Nationwide Children's Hospital in Columbus. Ohio. To generate subgenomic RSV replicon, three glycoprotein genes, those for SH. G. and F. from a full-length recombinant GFP-expressing (rg) RSV antigenomic cDNA were deleted. Tn their place, a blasticidin S deaminase (bsd) gene was inserted. Through multiple steps, the RSV replicon was established in Helm cells (395 Hela) or BHK cells (APC126). Both 395 HeLa and APC126 cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) containing 4500 mg/L D-glucose, L-glutamine, and llOmg/L sodium pyruvate (Invitrogen. Cat. #11995-040). The medium was further supplemented with 10% (v/v) fetal bovine serum (FBS) (Mediatech, Cat. #35-010-CV), 1% (v/v) penicillin/streptomycin (Mediatech. Cat. #30-002-Cl), and 10 pg/mL of Blasticidin (BSD) (Invivogen, Cat. code antbl-1). Cells were maintained at 37 °C in a humidified 5% CO? atmosphere.

[1442] Determination of 50% in hi bi lory concentration (ECVo). 90% inhibitory concentration (EC90) and 50% cytotoxic concentration (CC50) in RSV replicon cells were performed by the following procedure. On the first day, 5000 RSV replicon cells per well were plated in a 96-well plate. On the following day, compounds to be tested were solubilized in 100% DMSO to 100X the desired final testing concentration. Each compound

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PCT/US2014/051642 was serially diluted (1:3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cell culture media. A 10 pL sample of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to treat the RSV replicon cells in 96-well format. The final DMSO concentration was 1% (v/v). Cells were incubated with compounds for 7 days (for 395Hela) or 3 days (for APC126) at 37 °C in a 5% CO₂ atmosphere. In each assay, positive control that was previously characterized in the RSV replicon assay was included.

[1443] The Renilla Luciferase Assay System (Promega. Cat. #E2820) was used to measure anti-RSV replicon activity. Assay plates were set up as stated above. Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V. EC?o. the concentration of the drug required for reducing RSV replicon RNA by 50% in relation to the untreated cell control value, was calculated from the plot of percentage reductions of the optical density (OD) value against the drug concentrations using the Microsoft Excel forecast function.

|1444] 3 95 HeLa or APC126 cell proliferation assay (Promega; CellTiter-Glo

Luminescent Cell Viability Assay. Cat. #G7572) was used to measure cell viability. The CellTiter-Glo*' Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the ATP present, which signals the presence of metabolically active cells. Assay plates were set up in the same format as noted above for the replicon assay. CellTiter-Glo reagent (100 pL) was added to each well and incubated at room temperature for 8 minutes. Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V. The CC50. the concentration of the drug required for reducing viable cells by 50% in relation to the untreated cell control value, was calculated from the plot of percentage reductions of the luminescence value against the drug concentrations using the Microsoft Excel forecast function.

[1445] Table H includes compounds with an EC50 value that is less than 1 μΜ. Table I includes compounds with an EC50 value that is equal to or higher than 1 μΜ and less than 50 μΜ. Other tested compounds disclosed herein had an EC50 value of 50 μΜ or greater.

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PCT/US2014/051642

Table H

Compound
106
115
116
116b
117
117b
118
118 b
119
120
120b
122
122a
123
124
125
126
130
140
141
143
147
166
176
184
189
191
192
193
194
195
198
200
202
204
205
208
209
211
218
223

Compound
224
226
228
232
237
239
240
241
243
244
245
246
248
249
250
255
260
271
272
273
275
281
282
283
284
289
292
298
302
303
304
306
307
308
309
310
311
312
314
315
316

Compound
317
318
319
320
321
322

324
325
326
327
328
330
331
-> -> s
334
335
336
338
339
341
342
343
344
345
346
347
348
349
354
355
356
357
358
359
360
361
362
363
364
365

Compound
366
369
370
371
372
373
376
379
380
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
398
400
403
405
406
409
411
413
415
418
419
421
423
424
425
428
431

Compound

434

436

437

442

443

444

445

447

448

449

452

453

454

455

456

459

460

462

466

467

470

483

485

486

487

488

489

490

491

493

494

496

497

498

498d

499

500

501

502

503

504

-484WO 2015/026792

PCT/US2014/051642

Compound

505

506

507

508

509

510

511

514

515

516

519

520

521

523

524

525

526

527

528

529

530

531

532

Compound

533

534

535

536

538

539

540

542

543

545

546

547

548

550

551

552

554

555

556

558

560

561

562

Compound

563

564

567

569

571

572

574

575

576

577

578

579

580

581

583

584

585

586

588

589

590

594

595

Compound

596

598

600

601

602

603

604d

605d

611

612

614

615

621

622

623b

624b

626

627

630

633 b

634

635

636

Compound
637
638
640
641
642
643
644
645
646
647
650
651
653
659
663
664
665
667
672
675

Table 1

Compound

127

128

163

Compound

168

220 j 1 j

Compound

375

378

Compound

438

461

EXAMPLE 15 Combination Studies

RSV with Renilla Reporter [1446] RSV expressing Renilla luciferase (A2-RL-linel9F) was generated by Dr. Martin Moore of Emory University, Atlanta, GA. USA. The in vitro viral kinetics of A2-RLlinel 9F is similar to that of wild type RSV (See Hotard, A.L., Virology (2012) 434(1 ):129— 136).

-485WO 2015/026792

PCT/US2014/051642 [1447] Host cell HEp-2 was purchased from ATCC (Cat. &CCL-23) and cells were cultured in DMEM/Ilam’s F-12 50/50 lx containing L-glutamine and 15 mM IIEPES (Mediatech, Cat. #10-092-CM). The medium was further supplemented with 5% (v/v) FBS (Mediatech, Cat. #35-010-CV) and 1% (v/v) penicillin/streptomycin (Mediatech. Cat. #30-002-CI). HEp-2 cells were maintained at 37 °C in a humidified 5% CO₂ atmosphere. Drug Treatment and Viral Dosing [1448] To determine the effect of a combination of compounds, the following procedure w^ras followed. On the first day, 20.000 HEp-2 cells were plated per well in a 96well plate. On the following day. test articles were solubilized in 100% DMSO (for chemicals) or 1 x PBS (for biologies) to 200x the desired final testing concentration. Subsequently, Compound (A), or a pharmaceutically acceptable salt thereof, w'as serially diluted (1:3) to 9 distinct concentrations horizontally in a 96-well plate, and Compound (B), or a pharmaceutically acceptable salt thereof, was serially diluted (1:3) to 7 distinct concentrations vertically in 06-we 11 plate. The serially diluted 200x test articles were then diluted 1:10 into cell culture media to generate 20x test articles. A 5 μΙ. aliquot of the 20x test articles was added in a checkerboard lashion to the cells with 90 μΕ existing media. Space was also allotted for titrations of each of the compounds alone to be used as reference controls. After 12 hour pre-incubation of test articles, A2-RL-linel9F at an MOI of 0.5 was added to the plate and further incubated for 2 days at 37 °C in a 5% CO?.

Determination of Anti-RSV Activity [1449] The Renilla Luciferase Assay System (Promega, Cat. # E2820) was used to measure anti-RSV replicon activity. Assay plates were set up as stated above. Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V.

Cell Viability Assay [1450] Promega CellTiter-Glo Luminescent Cell Viability Assay, Cat. #G7572) was used to measure cell viability. The CellTiter-Glo Luminescent Cell Viability Assay is a homogeneous method to determine the number of viable cells in culture based on quantitation of the adenosine triphosphate (ATP) present, which signals the presence of metabolically active cells. Assay plates were set up in the same format the anti-RSV assay, except that no virus was added to the cell viability assay. A 100-pL aliquot of CellTiter-Glo

-486WO 2015/026792

PCT/US2014/051642 reagent was added to each well and incubated at room temperature for 8 minutes.

Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V.

Data Analysis [1451] Each experiment was performed at N=5 for both anti-RSV activity and cell viability. Mean percent inhibition of the replicon values from the 5 experiments was generated and for anti-RSV activity, it was analyzed using two drug interaction analysis models. Isobologram Analysis and/or Prichard's Model.

Isobologram Analysis [1452] The effects of drug-drug combinations were evaluated by the I.oewc additivity model in which the experimental data were analyzed using CalcuSyn (Biosoft. Ferguson. MO), a computer program based on the method of Chou and Talalay. The combination index (CI) value and the isobologram for each experimental combination w⁷ere calculated. CI values of <1, 1, and >1 indicate synergy, additive effect, and antagonism, respectively. Under the synergy category, CI<0.1 is considered very⁷ strong synergism; Cl 0.1-0.3 strong synergism; CI 0.3-0.7 synergism and CI 0.7-0.85 moderate synergism. The isobologram analysis, which graphically represents additive, synergistic, and antagonistic drug effects, was also used to model the interaction of antiviral activities. In this representation, an effective concentration (EC) value of one drug is plotted on one axis and corresponding EC value of a second drug is plotted on the second axis; the line connecting these two points represents the amount of each drug in a combination that would be required to reach the equivalent EC value, given that their effects are additive.

Prichard's Model (MacSynergy IT) [1453] MacSynergy IT software was kindly⁷ provided by Dr. M. Prichard (University of Michigan). This program allows the three-dimensional examination of drug interactions of all data points generated from the checkerboard combination of two inhibitors with Bliss-Independence model. Confidence bounds are determined from replicate data. If the 95% confidence limits (CL) do not overlap the theoretic additive surface, then the interaction between the two drugs differs significantly from additive. The volumes of synergy or antagonism can be determined and graphically depicted in three dimensions and represent the relative quantity of synergism or antagonism per change in the two drug

-487WO 2015/026792

PCT/US2014/051642 concentrations. Synergy and antagonism volumes are based on the Bliss independence model, which assumes that both compounds act independently on different targets. A set of predicted fractional responses faAB under the Bliss independence model is calculated as faAB = faA + faB - faA· faB with faA and faB representing the fraction of possible responses, e.g. % inhibition, of compounds A and B at amounts dA and dB, respectively, and describes the % inhibition of a combination of compounds A and B at amount (dA+dB). IffaAB > faA + faB faA· faB then we have Bliss synergy; if faAB < faA + faB - faA· faB then we have Bliss antagonism. The 95% synergy/antagonism volumes are the summation of the differences between the observed inhibition and the 95% confidence limit on the prediction of faAB under the Bliss independence model. MacSynergy II was used for data analysis.

[1454] MacSynergy II Volume Descriptions: <25 μΜ²% = Additive; 25-50 μΜ”% = Minor synergism; 50-100 μΜ~% = Significant synergism; and >100 μΜ % = Strong synergism. For the combination of 574 and BMS-433771 (a fusion protein inhibitor) had a synergy volume of 24.9 μΜ²% (additive/minor synergism).

EXAMPLE F

Parainfluenza virus-3 (P1V-3) Plaque Assay |1455] MA-104 cells are grown in 24-well plates to a confluency of 90% in the presence of minimal essential medium (MEM) supplemented with 10% fetal bovine serum and antibiotics (C-EMEM). The cells are then washed twice with non-complete minimal essential medium (NC-EMEM). Test articles are dissolved in DMSO to a stock concentration of 10 mM.

[1456] An aliquot of 0.5 mL of the test article at various concentrations are then inoculated in triplicate wells and are incubated for 60 mins at 37 °C with 5% CO₂ for the diffusion of test article into MA-104 cells. After the incubation period, a stock of human PIV type 3 are thawed and diluted with NC-EMEM to achieve a viral concentration of 10⁴pfu/mL. An aliquot of 0.1 mL are then inoculated into all the wells except for the negative and test article toxicity control wells. Upon infection, the plates are incubated for 72 h at 37 °C at 5% CO₂. After incubation, the plates are examined under microscopy to record cytotoxicity. The supernatants are collected for viral quantification using a standard plaque assay using MA-104 cells as the indicator cells.

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PCT/US2014/051642 [1457] To perform the plaques assay, MA-104 cells are grown to confluence in 24-well plates. The cells are washed with serum-free medium prior to inoculation of duplicate wells with serial 10-fold dilutions of supernatant sample. After 1 h incubation at 37 °C, the samples are aspirated and 1.0 mL of methyl cellulose overlay media are added to each well. After 6 days of culture, the cells are fixed and stained with 0.06% crystal violet in 1% glutaraldehyde and viral plaques are enumerated. The data are analyzed with Prism software with ECjo defined as drug concentration that reduced the viral load 50% from the viral control (VC).

EXAMPLE G

Human metapneumovirus (hMPV) TCIDgp Assay [1458] LLC-MK2 cells are grown in 24-wel 1 plates to a confluency of 90% in the presence of minimal essential medium (MEM) supplemented with 10% fetal bovine serum and antibiotics (C-EMEM). The cells are then washed twice with non-complete minimal essential medium (NC-EMEM). Test articles are dissolved in DMSO to a stock concentration of 10 mM.

[1459] An aliquot of 0.5 mL of the test article at various concentrations are then inoculated in triplicate wells and are incubated for 60 mins at 37 °C with 5% CO? for the diffusion of test article into LLC-MK2 cells. After the incubation period, a stock of human metapneumovirus are thawed and diluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. An aliquot of 0.1 mL are then inoculated into all the wells except for the negative and test article toxicity control wells. Upon infection, the plates are incubated for 7 days at 37 °C at 5% CCL. After incubation, the plates are examined under microscopy to record cytotoxicity. The supernatants are collected for viral quantification using a standard TCIDjo assay using LLC-MK2 cells as the indicator cells. The data are analyzed with Prism software with ECso defined as drug concentration that reduced the viral load 50% from the viral control (VC).

[1460] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made

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PCT/US2014/051642 without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein arc illustrative only and arc not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the invention.

-490-491 2014308991 04 Feb 2019

Claims

CLAIMS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:

wherein: L is selected from the group consisting of:

A is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted aryl(Ci-2 alkyl), an optionally substituted heteroaryl and an optionally substituted 5-18 membered heterocyclyl;

Y is selected from the group consisting of an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl;

R^la, R^lband R^ld are each independently hydrogen or an unsubstituted Cm alkyl;

R^2a and R^2al are each independently selected from the group consisting of hydrogen, an unsubstituted Cm alkyl, an optionally substituted aryl(Ci-6 alkyl), an optionally substituted heterocyclyl(Ci-6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or

-492 2014308991 04 Feb 2019

R^2al is hydrogen, and R^la and R^2a together with the atoms to which they are attached form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl,

R^2b and R^2bl are each independently selected from the group consisting of hydrogen, an optionally substituted Cm alkyl, an optionally substituted aryl(Ci-6 alkyl), an optionally substituted heterocyclyl(Ci-6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy; or

R^2bl is hydrogen, and R^lb and R^2b together with the atoms to which they are attached form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl;

R^2d and R^2dl are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-4 alkyl, an optionally substituted aryl(Ci-6 alkyl), an optionally substituted heterocyclyl(Ci-6 alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl and hydroxy;

........between X^la and X^2a represents a single or double bond between X^la and X^2a;......

— between X^2a and X^3a represents a single or double bond between X^2a and X^3a; provided that — — between X^la and X^2a and........between X^2a and X^3a cannot be both double bonds and at least one of........is a double bond;

when........between X^la and X^2a represents a double bond and........between X^2a and

X^3a is a single bond, then X^la is N or CR^4al, X^2a is N or CR^5a and X^3a is NR^6al or CR^6a2R^6a3; and when........between X^la and X^2a represents a single bond and........between X^2a and X^3a is a double bond, then X^la is NR^4a or CR^4a2R^4a3, X^2a is N or CR^5a and X^3a is N or CR^6a; or

X^la, X^2a and X^3a are each independently C or N and form a ring or ring system selected from an optionally substituted 6-membered heteroaryl, an optionally substituted bi-cyclic heteroaryl, and an optionally substituted heterocyclyl by joining X^la and X^3a together; with the proviso that the valencies of X^la, X^2a and X^3a are each independently satisfied with a substituent selected from hydrogen and an optionally substituted C1-4 alkyl, and X^la, X^2a and X^3a are uncharged;

-493 R^3a is selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C2-4 alkenyl, an optionally substituted C₂m alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Cm alkoxy, -O-carboxy, an optionally

2014308991 04 Feb 2019 substituted heteroaryl, an optionally substituted heterocyclyl, CHF2, CF3 and

R^3al is selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C1-4 alkyl, an optionally substituted C₂m alkenyl, an optionally substituted C2-4 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C1-4 alkoxy, -O carboxy, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, CHF₂, CF3 and , provided that R^3a and R^3al cannot be both hydrogen; or

R^3a and R^3al together form =N-OR^a; or R^3a and R^3al together with the atom to which they are attached form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, or an optionally substituted 5 membered ring;

R^4a, R^4al, R^4a2 and R^4a3 are each independently hydrogen or an unsubstituted Cm alkyl;

R^5a is hydrogen or an unsubstituted C1-4 alkyl;

R^6a and R^6al are each independently hydrogen, an optionally substituted C1-4 alkyl or an optionally substituted alkoxyalkyl;

R^6a2 and R^6a3 are each independently hydrogen or an unsubstituted C1-4 alkyl;

X^lb, X^2b and X^3b are each independently C, N, or O and form a bi-cyclic ring selected from an optionally substituted 9-membered bi-cyclic heteroaryl, an optionally substituted 10membered bi-cyclic heteroaryl, and an optionally substituted 10-membered bi-cyclic heterocyclyl by joining X^lb and X^3b together, wherein ........ between X^lb and X^2b represents a single or double bond between X^lb and X^2b; ........between X^2b and X^3b represents a single or double

2014308991 04 Feb 2019

-494bond between X^2b and X^3b; and provided that at least one of X^lb, X^2b and X^3b comprises a nitrogen atom and both........cannot be double bonds; with the proviso that the valencies of X^lb,

X^2b and X^3b are each independently satisfied with a substituent selected from hydrogen and an optionally substituted Cm alkyl; and X^lb, X^2b and X^3b are uncharged;

R^ais hydrogen or an unsubstituted Cm alkyl;

m^d is 1;

ring B^d is an optionally substituted C5 cycloalkyl; and ring B^dl is an optionally substituted pyridinyl;

0.

provided that the compound is not
2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein L is Formula (la).
3. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein X^la is CR^4al or CR^4a2R^4a3, X^2a is N, and X^3a is CR^6a or CR^6a2R^6a3.
4. The compound of Claim 2, or a pharmaceutically acceptable salt thereof, wherein

........between X^la and X^2a is a single bond,........between X^2a and X^3a is a double bond, X^la is CR^4a2R^4a3, X^2a is N, and X^3a is CR^6a; or wherein........between X^la and X^2a is a double bond, —

.....between X^2a and X^3a is a single bond, X^la is CR^4al, X^2a is N, and X^3a is CR^6a2R^6a3; or wherein -X^la......X^2a......X^3a- is -CH2-N=CH- or -CH=N-CH2-; or wherein -X^la......X^2a......X^3a- is N=N-CH2-, -N=CH-CH₂- or -N=CH-NH-; or wherein -X^la......X^2a......X^3a- is -CH₂-CH=N-, NH-CH=NH- or -NH-N=CH-.

-495 5. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

2014308991 04 Feb 2019

L is Formula (Ial):

6. The compound of Claim 5, or a pharmaceutically acceptable salt thereof, wherein X^la, X^2a and X^3a form a ring or ring system that is an optionally substituted 6membered heteroaryl or an optionally substituted bi-cyclic heteroaryl; or wherein X^la, X^2a and X^3a form a ring or ring system that is an optionally substituted mono-cyclic heterocyclyl or an optionally substituted bi-cyclic heterocyclyl; or wherein X^la, X^2a and X^3a form a ring or ring system selected

ΧΧγΥ from the group consisting of an optionally substituted , an optionally substituted , an optionally substituted an optionally substituted an optionally substituted , an optionally substituted , an optionally substituted and an optionally substituted ; wherein each — — is independently absent or a bond; each R^A5, each R^A6 and each R^A7 are independently an unsubstituted Ci-6 alkyl, halogen, hydroxy, amino, mono-substituted amino, di-substituted amino or -NH-S(=O)Ci-4 alkyl; and R^A8 is hydrogen or an unsubstituted Ci-6 alkyl.

7. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is Formula (Ia2):

-496 2014308991 04 Feb 2019 wherein R^7al, R^7a2 and R^7a3 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted Ci-s alkyl, an optionally substituted C₂-8 alkenyl, an optionally substituted C2-8 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C1-8 alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(Ci-8 alkyl), haloalkyl, an optionally substituted O-amido and an optionally substituted Ccarboxy.

8. The compound of Claim 7, or a pharmaceutically acceptable salt thereof, wherein R^7al is a Cm alkoxy, and R^7a2 and R^7a3 are both hydrogen; or wherein R^7al is a hydrogen, R^7a2 is an optionally substituted Cm alkyl, and R^7a3 is hydrogen, wherein then the Cm alkyl of R^7a2 is substituted, it is substituted with a substituent selected from the group consisting of halo, hydroxy, Cm alkoxy, an optionally substituted aryl(CM alkyl), an optionally substituted Ccarboxy, amino, an optionally substituted mono-substituted amino, an optionally substituted disubstituted amino, an optionally substituted C-amido, an optionally substituted N-amido, an optionally substituted N-carbamyl, an optionally substituted N-sulfonamido, an optionally substituted urea, an optionally substituted amidine and an optionally substituted acetylurea; or wherein R^7al is a hydrogen, R^7a2 is an optionally substituted heterocyclyl, and R^7a3 is hydrogen; or wherein R^7al is a mono-substituted amino, and R^7a2 and R^7a3 are both hydrogen.

9. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein L is Formula (Ia3):

2014308991 04 Feb 2019 wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl; and R^8a3 is selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted Ci-8 alkyl, an optionally substituted C2-8 alkenyl, an optionally substituted C2-8 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C1-8 alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(Ci-8 alkyl), haloalkyl and an optionally substituted C-carboxy.

10. The compound of Claim 9, or a pharmaceutically acceptable salt thereof, wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered cycloalkyl or an optionally substituted 6-membered cycloalkyl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted aryl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered heteroaryl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heterocyclyl or an optionally substituted 6-membered heterocyclyl.

11. The compound of Claim 9, or a pharmaceutically acceptable salt thereof, wherein in Formula (Ia3) is an optionally substituted , an optionally

-498 2014308991 04 Feb 2019 (R^A7)cm

N(R^as) ; wherein each —

- is independently absent or a bond; each R^A5, each R^A6 and each R^A7 are independently halogen, an unsubstituted Ci-6 alkyl, hydroxy, amino, an optionally substituted mono-substituted amino, an optionally substituted di-substituted amino, -(CH2)i-4OH, -(CH2)i-4NH₂ or N-sulfmamido, or two R^as, two R^A6 or two R^A7 are taken together to form an optionally substituted 5- membered ring to an optionally substituted 6-membered ring; and R^A8 is hydrogen or an unsubstituted Ci-6 alkyl.

12. The compound of any one of Claims 2-11, or a pharmaceutically acceptable salt thereof, wherein R^la is hydrogen; or wherein R^la is an unsubstituted Cm alkyl.

13. The compound of any one of Claims 2-12, or a pharmaceutically acceptable salt thereof, wherein R^2a and R^2al are both hydrogen; or wherein R^2a is hydrogen, and R^2al is an unsubstituted Cm alkyl; or wherein R^2a is hydrogen, and R^2al is an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(Ci_6 alkyl); or wherein R^2a is hydrogen, and R^2alis an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy; or wherein R^2a and R^2al are both an unsubstituted C1-4 alkyl.

14. The compound of any one of Claims 2-11, or a pharmaceutically acceptable salt thereof, wherein R^2al is hydrogen, and R^la and R^2a together with the atoms to which they are attached form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.

15. The compound of any one of Claims 2-14, or a pharmaceutically acceptable salt thereof, wherein R^3a is hydrogen, and R^3al is selected from the group consisting of amino, an unsubstituted Cm alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C3-6 cycloalkyl, an unsubstituted Cm alkoxy, hydroxy, halogen and an unsubstituted heteroaryl; or wherein R^3a is hydrogen, and R^3al is hydroxy; or wherein R^3a is hydroxy, and R^3al is selected from the group consisting of amino, an unsubstituted C m alkyl, an unsubstituted C₂a alkenyl, an unsubstituted C2+ alkynyl, an unsubstituted C3-6 cycloalkyl, an

-499 -

2014308991 04 Feb 2019 unsubstituted Cm alkoxy, hydroxy, halogen, -O-carboxy, an unsubstituted heteroaryl and an optionally substituted heterocyclyl; or wherein R^3a is hydroxy, and R^3al is an unsubstituted Cm alkyl; or wherein R^3a is hydroxy, and R^3al is an unsubstituted C2-4 alkynyl; or wherein R^3a is hydroxy, and R^3al is CF3; or wherein R^3a is hydroxy, and R^3al is CHF2; or wherein R^3a is halogen, and R^3al is CF3; or wherein R^3a is halogen, and R^3al is CHF2; or wherein R^3a is hydroxy, and R^3alis an unsubstituted C3_6 cycloalkyl; or wherein R^3a is halogen, and R^3al is an unsubstituted C3-6 cycloalkyl; or wherein R^3a and R^3al are both halogen; or wherein R^3a is hydrogen, and R^3al is unsubstituted Cm alkyl; or wherein R^3a is an unsubstituted Cm alkoxy, and R^3al is an unsubstituted Cm alkyl; or wherein R^3al is a substituted Cm alkyl substituted with a substituent selected from the group consisting of halogen, hydroxy, amino, mono-substituted amino, disubstituted amino, -N-amido, an optionally substituted mono-cyclic heteroaryl and an optionally substituted mono-cyclic heterocyclyl; and R^3a is hydroxy; or wherein one of R^3a and R^3al is an optionally substituted mono-cyclic heteroaryl or an optionally substituted mono-cyclic heterocyclyl; and the other of R^3a and R^3al is hydroxy; or wherein one of R^3a and R^3al is selected from the group consisting of an optionally substituted imidazole, an optionally substituted pyrazole, an optionally substituted pyrrolidine, an optionally substituted piperidine, an optionally substituted piperazine, an optionally substituted morpholine, an optionally substituted triazole, an optionally substituted piperazinone and an optionally substituted azetidine; and the other of R^3aand R^3al is hydroxy; or wherein R^3a and R^3al together form N=OR^a; or wherein R^3a and R^3altogether with the atom to which they are attached form an optionally substituted 3 to 5 membered ring.

16. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is Formula (lb):

17. The compound of Claim 16, or a pharmaceutically acceptable salt thereof, wherein the bi-cyclic ring is an optionally substituted 9-membered bi-cyclic heteroaryl or an optionally

-500-

2014308991 04 Feb 2019 substituted 10-membered bi-cyclic heteroaryl; or wherein the bi-cyclic ring is an optionally substituted 10-membered bi-cyclic heterocyclyl.

18. The compound of Claim 16 or Claim 17, or a pharmaceutically acceptable salt thereof, wherein X^lb is C, X^2b is N, and X^3b is C; or wherein X^lb is N, X^2b is N, and X^3b is C; or wherein X^lb is N or C, X^2b is O, and X^3b is N or C.

19. The compound of Claim 16, or a pharmaceutically acceptable salt thereof, wherein the bi-cyclic ring is an optionally substituted an optionally substituted , an optionally substituted and an optionally substituted ; wherein each is independently absent or a bond; each R^B1, each R^B2 and each R^B3 are independently an unsubstituted Ci-6 alkyl, halogen, hydroxy, amino, monosubstituted amino, di-substituted amino or -NH-S(=O)Cm alkyl; and R^B4 is hydrogen or an unsubstituted Ci-6 alkyl.

20. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

L is Formula (lb 1):

-501 2014308991 04 Feb 2019 wherein: the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted cycloalkenyl an optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyciyl; and R^4b3 is selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted Ci-8 alkyl, an optionally substituted C₂-8 alkenyl, an optionally substituted C2-8 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyciyl, an optionally substituted hydroxyalkyl, an optionally substituted C1-8 alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(Ci-8 alkyl), haloalkyl and an optionally substituted C-carboxy.

21. The compound of Claim 20, or a pharmaceutically acceptable salt thereof, wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered cycloalkenyl or an optionally substituted 6-membered cycloalkenyl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted aryl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heteroaryl or an optionally substituted 6-membered heteroaryl; or wherein the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted 5-membered heterocyciyl or an optionally substituted 6-membered heterocyciyl.

22. The compound of any one of Claims 16-21, or a pharmaceutically acceptable salt thereof, wherein R^lb is hydrogen; or wherein R^lb is unsubstituted Cm alkyl.

23. The compound of any one of Claims 16-21, or a pharmaceutically acceptable salt thereof, wherein R^2b and R^2bl are both hydrogen; or wherein R^2b is hydrogen, and R^2bl is an optionally substituted Cm alkyl; or wherein R^2b is hydrogen, and R^2bl is an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(Ci-6 alkyl); or wherein R^2b is hydrogen, and R^2bl is an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy; or wherein R^2b and R^2blare both an optionally substituted C1-4 alkyl.

24. The compound of any one of Claims 16-21, or a pharmaceutically acceptable salt thereof, wherein R^2bl is hydrogen, and R^lb and R^2b together with the atoms to which they are

-502 -

2014308991 04 Feb 2019 attached form an optionally substituted 5 membered heterocyclyl or an optionally substituted 6 membered heterocyclyl.

25. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein

R^1d

L is Formula (Id): 6 R^2d

26. The compound of Claim 25, or a pharmaceutically acceptable salt thereof, wherein R^ld is hydrogen; or wherein R^ld is unsubstituted Ch alkyl.

27. The compound of Claim 25 or Claim 26, or a pharmaceutically acceptable salt thereof, wherein R^2d and R^2dl are both hydrogen; or wherein R^2d is hydrogen, and R^2dl is an optionally substituted C1-4 alkyl; or wherein R^2d is hydrogen, and R^2dl is an optionally substituted aryl(Ci-6 alkyl) or an optionally substituted heterocyclyl(Ci-6 alkyl); or wherein R^2d is hydrogen, and R^2dl is an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl or hydroxy; or wherein R^2d and R^2dlare both an optionally substituted C1-4 alkyl.

28. The compound of any one of Claims 1-27, or a pharmaceutically acceptable salt thereof, wherein A is an optionally substituted aryl; or wherein A is an optionally substituted phenyl; or wherein A is a phenyl substituted with one or more substituents selected from the group consisting of: an unsubstituted C1-4 alkyl, a substituted Ci_₄ alkyl, cycloalkyl, hydroxy, a substituted Cm alkoxy, an unsubstituted Cm alkoxy, halogen, haloalkyl, an optionally substituted haloalkoxy, nitro, amino, mono-substituted amine, di-substituted amine, -O-amido, sulfenyl, alkyoxyalkyl, an optionally substituted aryl, an optionally substituted mono-cyclic heteroaryl, an optionally substituted mono-cyclic heterocyclyl, an optionally substituted aryl (Cm alkyl), an optionally substituted monocyclic heteroaryl(Cm alkyl), an optionally substituted monocyclic heterocyclyl(CM alkyl), hydroxyalkyl and aminoalkyl; or wherein A is a phenyl substituted with one or more substituents selected from the group consisting of: methyl, ethyl, propyl, butyl, hydroxy, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, t-butoxy, phenoxy, bromo, chloro, fluoro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, cyano, N,N-di-503 methyl-amine, N,N-di-ethyl-amine, N-methyl-N-ethyl-amine, N-methyl-amine, N-ethyl-amine,

2014308991 04 Feb 2019 amino, N-amido, N-sulfonamido, alkylthio, an optionally substituted phenyl, an optionally substituted imidazole, an optionally substituted morpholinyl, an optionally substituted pyrazole, an optionally substituted pyrrolidinyl, an optionally substituted pyridinyl, an optionally substituted piperidinyl, an optionally substituted piperidinone, an optionally substituted pyrrolidinone, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted 1,2,4-oxadiazole, -(CH2)i-4-OH, -(CH2)i-2-NH(CH3), an optionally substituted -(CH2)i-2-imidazole, an optionally substituted -(CH2)i-2-pyrrolidinone, an optionally substituted -(CH2)i-2-imidazolidinone, -O(CH2)2-NH2, -O(CH2)2-NH(CH3), -O(CH2)2-N(CH3)2, O-(CH₂)₂-4OH, -O(CH₂)₂OCH3, an optionally substituted -0(CH2)o-2-cyclopentanone, an optionally substituted -0(CH2)o-2pyrrolidinone, an optionally substituted -0(CH2)o-2-morpholinyl, an optionally substituted -0(CH2)o-2-triazole, an optionally substituted -0(CH2)o-2-imidazole, an optionally substituted -0(CH2)o-2-pyrazole, an optionally substituted -0(CH2)o-2-tetrahydrofuran, an optionally substituted -0(CH2)o-2-pyrrolidinone, an optionally substituted -0(CH2)o-2-tetrazole,

HO

-504-

2014308991 04 Feb 2019 ^H°N

H₂N . _{or w}herein A is a di-substituted phenyl; or wherein A is an optionally substituted cycloalkyl or an optionally substituted cycloalkenyl; or wherein A is an optionally substituted aryl(Ci-2 alkyl); or wherein A is an optionally substituted heteroaryl; or wherein A is an optionally substituted heteroaryl, wherein the heteroaryl is selected from the group consisting of: an optionally substituted imidazole, an optionally substituted thiazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyridine, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted quinolone, an optionally substituted imidazole, an optionally substituted oxazole, an optionally substituted isoxazole, an optionally substituted benzoimidazole, an optionally substituted benzooxazole, an optionally substituted benzothiazole and an optionally substituted imidazo[l,2-a]pyrimidine; or wherein A is an optionally substituted 5-18 membered heterocyclyl; or wherein A is an optionally substituted 5-18 membered heterocyclyl, wherein the 5-18 membered heterocyclyl is selected from the group consisting of: an optionally substituted

H

Cte A optionally substituted

-505 2014308991 04 Feb 2019

29. The compound of any one of Claims 1-28, or a pharmaceutically acceptable salt thereof, wherein Y is an optionally substituted aryl; or wherein Y is a mono-substituted phenyl; or wherein Y is a di-substituted phenyl; or wherein Y is an optionally substituted mono-cyclic heteroaryl; or wherein Y is an optionally substituted mono-cyclic heteroaryl, wherein the optionally substituted mono-cyclic heteroaryl is selected from the group consisting of: an optionally substituted imidazole, an optionally substituted furan, an optionally substituted thiophene, an optionally substituted pyrrole, an optionally substituted pyrimidine, an optionally substituted pyrazine, an optionally substituted pyridine, an optionally substituted pyrazole, an optionally substituted oxazole, an optionally substituted isoxazole and an optionally substituted thiazole; or wherein Y is an optionally substituted bi-cyclic heteroaryl; or wherein Y is an optionally substituted bi-cyclic heteroaryl, wherein the optionally substituted bi-cyclic heteroaryl is selected from the group consisting of: an optionally substituted benzothiophene, an optionally substituted benzofuran, an optionally substituted indole, an optionally substituted quinoline, an optionally substituted isoquinoline, an optionally substituted benzooxazole, an optionally substituted benzoisoxazole, an optionally substituted benzoisothiazole, an optionally substituted benzothiazole, an optionally substituted benzoimidazole, an optionally substituted benzotriazole, an optionally substituted ΙΗ-indazole, an optionally substituted 2H-indazole, an optionally substituted

N , an optionally substituted

N , an optionally substituted

HN an optionally substituted ^ς Nan optionally substituted an optionally substituted

S , an optionally substituted and an optionally

-506 2014308991 04 Feb 2019 substituted S ; or wherein Y is an optionally substituted heterocyclyl; or wherein Y is an optionally substituted heterocyclyl, wherein the optionally substituted heterocyclyl is selected from the group consisting of: an optionally substituted pyridinone, an optionally substituted substituted optionally substituted cycloalkenyl.

30. The compound of any one of Claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Y is unsubstituted.

31. The compound of any one of Claims 1-29, or a pharmaceutically acceptable salt thereof, wherein Y is substituted with one or more R^B, wherein each R^B is independently selected from the group consisting of: cyano, halogen, an optionally substituted Cm alkyl, an unsubstituted C₂-4 alkenyl, an unsubstituted C2-4 alkynyl, an optionally substituted aryl, an optionally substituted 5 or 6 membered heteroaryl, an optionally substituted 5 or 6 membered heterocyclyl, hydroxy, C1-4 alkoxy, alkoxyalkyl, C1-4 haloalkyl, haloalkoxy, an unsubstituted acyl, an optionally substituted -C-carboxy, an optionally substituted -C-amido, sulfonyl, carbonyl, amino, mono-substituted amine, di-substituted amine and

O

2014308991 04 Feb 2019

-507 -

32. The compound of any one of Claims 1-28 and 31, or a pharmaceutically acceptable salt thereof, wherein Y is an optionally substituted benzothiophene; or wherein Y is an optionally substituted benzoforan or an optionally substituted indole.

33. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

-508 -

2014308991 04 Feb 2019

2014308991 04 Feb 2019

-5102014308991 04 Feb 2019

-511 2014308991 04 Feb 2019

2014308991 04 Feb 2019

2014308991 04 Feb 2019

-5142014308991 04 Feb 2019

-515 2014308991 04 Feb 2019

Ο

Ο

2014308991 04 Feb 2019

-5172014308991 04 Feb 2019

-5182014308991 04 Feb 2019

-5192014308991 04 Feb 2019

-5202014308991 04 Feb 2019

O o

2014308991 04 Feb 2019

-522 2014308991 04 Feb 2019

2014308991 04 Feb 2019

-5242014308991 04 Feb 2019

O'

NH

H₃cA

- 525 2014308991 04 Feb 2019

-526 2014308991 04 Feb 2019

O och₃

2014308991 04 Feb 2019

-5282014308991 04 Feb 2019

2014308991 04 Feb 2019

530 2014308991 04 Feb 2019

-531 Feb 2019

-532 2014308991 04 Feb 2019

2014308991 04 Feb 2019

- 534 2014308991 04 Feb 2019

-535 2014308991 04 Feb 2019

2014308991 04 Feb 2019

-536 -

-537 2014308991 04 Feb 2019

Cl nh₂ (A

X/N(CH₃)₂

HN s=o nh₂ ch₃

-538 2014308991 04 Feb 2019

-539 2014308991 04 Feb 2019

-5402014308991 04 Feb 2019 o

Ό

H₂N

-541 2014308991 04 Feb 2019

-542-

2014308991 04 Feb 2019 h₂n

H₂N

2014308991 04 Feb 2019

-5442014308991 04 Feb 2019

O //

2014308991 04 Feb 2019

-546 2014308991 04 Feb 2019

-5472014308991 04 Feb 2019

-548 2014308991 04 Feb 2019

2014308991 04 Feb 2019

-5502014308991 04 Feb 2019

H₂N

-551 2014308991 04 Feb 2019

2014308991 04 Feb 2019

-553 2014308991 04 Feb 2019

-554-

2014308991 04 Feb 2019

-555 2014308991 04 Feb 2019

NH

-5562014308991 04 Feb 2019

-557 2014308991 04 Feb 2019

- 558 2014308991 04 Feb 2019

2014308991 04 Feb 2019 foregoing; or wherein the compound of Formula (I) is selected from the group consisting of:

-5602014308991 04 Feb 2019 a pharmaceutically acceptable salt of any of the foregoing; or wherein the compound of Formula

-561 2014308991 04 Feb 2019

Ό and CH3 _{5 or a} pharmaceutically acceptable salt of any of the foregoing.

34. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

35. Use of an effective amount of a compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 34 in the preparation of a medicament for ameliorating or treating a paramyxovirus infection; in the preparation of a medicament for inhibiting replication of a paramyxovirus; or in the preparation of a medicament for contacting a cell infected with a paramyxovirus.

36. Use of an effective amount of a compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 34 in the

-562 -

2014308991 04 Feb 2019 preparation of a medicament for ameliorating or treating a paramyxovirus infection in combination with one or more additional agents.

37. A method of ameliorating or treating a paramyxovirus infection; inhibiting replication of a paramyxovirus; or contacting a cell infected with a paramyxovirus, comprising administering to a subject in need of treatment an effective amount of a compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 34.

38. The use of Claim 35 or the method of Claim 37, wherein the paramyxovirus is a human respiratory syncytial virus.

39. A method of ameliorating or treating a paramyxovirus infection, comprising administering to a subject in need of treatment an effective amount of a compound of any one of Claims 1-33, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 34 in combination with one or more additional agents.

40. The use of claim 36 or the method of Claim 39, wherein the paramyxovirus is a human respiratory syncytial virus; and wherein the one or more additional agents is selected from the group consisting of an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, an interferon and another compound that inhibits the RSV vims, or a pharmaceutically acceptable salt of any of the foregoing.

41. The use or method of Claim 40, wherein the one or more additional agents is selected from the group consisting of RSV-IGIV, palivizumab, motavizumab, l-cyclopropyl-3[[l-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(l,3,5)triazin-2-ylamino}biphenyl-2,2 -disulfonic-acid (RFI-641), 4,4'-Bis[4,6-di[3-aminophenyl-N,N-bis(2carbamoylethyl)-sulfonilimino]-l,3,5-triazine-2-ylamino]-biphenyl-2,2'-disulfonic acid, disodium salt (CL387626), 2-[[2-[[ 1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-lH-benzimidazol-lyl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-l-yl]methyl]-6methylpyridin-3-ol (TMC-353121), 5,5 '-bis[ 1 -(((5-amino-1 H-tetrazolyl)imino)methyl)]2,2 ',4-563 2014308991 04 Feb 2019 methylidynetrisphenol (VP-14637, MDT-637), N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6methyl-[l,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (Pl 3), 2-((2-((1-(2aminoethyl)piperidin-4-yl)amino)-4-methyl-lH-benzo[d]imidazol-l-yl)methyl)-6-methylpyridin-

3- ol (R170591), l,4-bis(3-methylpyridin-4-yl)-l,4-diazepane (C15), (R)-9b-(4-chlorophenyl)-l- (4-fluorobenzoyl)-2,3-dihydro-lH-imidazo[l',2':l,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-l-yl)-6-methylpyrazolo[l,5-a]pyrimidin-2-yl)piperidine-lcarbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor, (S)-1 -(2-fluorophenyl)-3 -(2-oxo-5-phenyl-2,3 -dihydro-lHbenzo[e][l,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][l]benzazepine-2-carboxamide (YM-53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-l-yl)benzamido)benzoyl)-5,6,7,10tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide. 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4methyl-3-nitrophenyl)-lH-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ27, ribavirin, 5ethynyl-1 -beta-D-ribofiiranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-Dribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1 -((2R,3R,4S,5R)-3,4-dihydroxy-5(hydroxymethyl)tetrahydrofiiran-2-yl)-1 Η-1,2,4-triazole-3 -carboximidamide (T aribavirin, viramidine), l,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy -

4- (oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7 - methyl-3-oxo-l,3-dihydro-2-benzoforan-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-lH-2-benzofiiran-5-yl)-4methylhex-4-enoate (Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide, 5-methyl-N-[4-(trifluoromethyl) phenyl]isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((l-(4-methoxyphenyl)lH-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CC10 (CG-100), high titer, human immunoglobulin (RI-001), a nonneutralizing mAb against the G protein (mAb 131-2G), ALN-RSV01, ALN-RSV02, Medi-559, Medi-534 and Medi-557, or a pharmaceutically acceptable salt of any of the foregoing.

WO 2015/026792

PCT/US2014/051642

1/9

WO 2015/026792

PCT/US2014/051642

2/9

WO 2015/026792

PCT/US2014/051642

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WO 2015/026792

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9/9

ALIOS079WO_Sequence_Listing.txt

SEQUENCE LISTING <110> Alios BioPharma, Inc.

Wang, Guangyi

Beigelman, Leonid

Truong, Anh

Napolitano, Carmela

Andreotti, Daniele

He, Haiying

Stein, Karin Ann <120> ANTIVIRAL COMPOUNDS <130> ALIOS.079WO <140> Unassigned <141> 2014-08-19 <150> US 61/868519 <151> 2013-08-21 <150> US 61/945048 <151> 2014-02-26 <160> 4 <170> FastSEQ for Windows Version 4.0 <210> 1 <211> 28 <212> PRT <213> Artificial Sequence <220>

<223> Core polypeptide <400> 1

Asp Glu Phe Asp Ala Ser Ile Ser Gln Val Asn Glu Lys Ile Asn Gln 1 5 10 15 Ser Leu Ala Phe Ile Arg Lys Ser Asp Glu Leu Leu

20 25 <210> 2 <211> 35 <212> PRT <213> Artificial Sequence <220>

<223> Core polypeptide <400> 2

Phe Asp Ala Ser Ile Ser Gln Val Asn Glu Lys Ile Asn Gln Ser Leu 1 5 10 15 Ala Phe Ile Arg Lys Ser Asp Glu Leu Leu His Asn Val Asn Ala Gly 20 25 30

Lys Ser Thr <210> 3

Page 1

ALIOS079WO_Sequence_Listing.txt <211> 21 <212> DNA <213> Artificial Sequence <220>

<223> Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 3 ggcucuuagc aaagucaagt t <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220>

<223> Combined DNA/RNA Molecule: Synthetic oligonucleotide <400> 4 cuugacuuug cuaagagcct t

Page 2